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DENDRIMERS HAVING THIOPHOSPHORAMIDATE PATTERNS AND DERIVATIVES

20240116963 ยท 2024-04-11

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to new dendrimers with thiophosphoramidate units and derivatives, their preparation method and their use.

    Claims

    1. An n generation dendrimer or the pharmaceutically acceptable salts thereof, comprising: a central core ? of valence m, where m is an integer greater than or equal to 1; branching generation chains around the core, represented by formula (CG): ##STR00245## wherein A is O or S; B is aryl or heteroaryl, optionally substituted by C1-C6 alkyl or halo; D is selected from C1-C12 alkyl, C1-C12 haloalkyl, aryl, heteroaryl, (CH.sub.2CH.sub.2O).sub.aCH.sub.3, CH.sub.2(CH.sub.2CH.sub.2O).sub.aCH.sub.3, (CH.sub.2).sub.bNRR and CH.sub.2(CH.sub.2CH.sub.2O).sub.cNRR, where a, b and c are, independently of one another, integers of between 1 and 12, and R and R are, independently of one another, selected from H, C1-C12 alkyl, C1-C12 haloalkyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, tert-butylcarbonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethylsulfonyl, allyl, benzyl, trityl, ##STR00246## where Z.sup.1 is a single bond or a linear or branched hydrocarbon chain having 1 to 6 chain members, one or more chain members optionally being a heteroatom, and R.sup.1 and R.sup.2 are, independently of one another, selected from H, C1-C6 alkyl and M.sup.+, where M.sup.+ is a cation; E is O or S; an intermediate chain at the end of each generation chain represented by the formula (CI):
    -G-J-L-(CI) wherein G is O or S; J is aryl or heteroaryl, optionally substituted by C1-C6 alkyl or halo; L is a linear or branched hydrocarbon chain having 1 to 6 chain members, one or more chain members optionally being a heteroatom; an end group at the end of each intermediate chain represented by the formula (T): ##STR00247## wherein V is CH or N; W.sup.1 is H, C1-C12 alkyl or ##STR00248## where Z.sup.1 is a single bond or a linear or branched hydrocarbon chain having 1 to 6 chain members, one or more chain members optionally being a heteroatom, and R.sup.1 and R.sup.2 are, independently of one another, selected from H, C1-C6 alkyl and M.sup.+, where M.sup.+ is a cation; W.sup.2 is C1-C12 alkyl or ##STR00249## where Z.sup.1 is a single bond or a linear or branched hydrocarbon chain having 1 to 6 chain members, one or more chain members optionally being a heteroatom, and R.sup.1 and R.sup.2 are, independently of one another, selected from H, C1-C6 alkyl and M.sup.+, where M.sup.+ is a cation; wherein n is an integer of between 1 and 12.

    2. The dendrimer according to claim 1, wherein the central core ? is selected from pentoses, hexoses, and the groups of the following formulae: ##STR00250##

    3. The dendrimer according to claim 1 wherein m is equal to 6.

    4. The dendrimer according to claim 1 wherein that n is an integer between 1 and 5.

    5. The dendrimer according to claim 1 wherein in formula (CG), A is O.

    6. The dendrimer according to claim 1 wherein in formula (CG), B is phenyl, optionally substituted by C1-C6 alkyl or halo.

    7. The dendrimer according to claim 1 wherein in formula (CG), E is S.

    8. The dendrimer according to claim 1 wherein in formula (CI), G is O.

    9. The dendrimer according to claim 1 wherein in formula (CI), J is phenyl, optionally substituted by C1-C6 alkyl or halo.

    10. The dendrimer according to claim 1 wherein in formula (CI), L is (CH.sub.2).sub.d, where d is an integer between 1 and 6.

    11. The dendrimer according to claim 1 wherein in formula (T), V is N.

    12. The dendrimer according to claim 1 wherein in formula (T), W.sup.1 is H and W.sup.2 is C1-C12 alkyl.

    13. The dendrimer according to claim 1 wherein in formula (T), W.sup.1 and W.sup.2 are ##STR00251## where Z.sup.1 is a single bond or a linear or branched hydrocarbon chain having 1 to 6 chain members, and R.sup.1 and R.sup.2 are, independently of one another, selected from H, C1-C6 alkyl and M.sup.+, where M.sup.+ is a cation of an element from group IA, IIA, IIB or IIIA of the periodic table of the elements, or a cation of a nitrogenous base, preferably M.sup.+ is Na.sup.+ or K.sup.+.

    14. The dendrimer according to claim 1 represented by the following formula (II): ##STR00252## or the pharmaceutically acceptable salts thereof, wherein ?, A, B, D, E, G, J, L, W.sup.2, m and n are as defined in claim 1, and { }.sub.n denotes the branching structure of the n generation chains of said dendrimer.

    15. The dendrimer according to claim 1 represented by the following formula (III): ##STR00253## or the pharmaceutically acceptable salts thereof, wherein ?, A, B, D, E, G, J, L, V, Z.sup.1, R.sup.1, R.sup.2, m and n are as defined in claim 1, and { }.sub.n denotes the branching structure of the n generation chains of said dendrimer.

    16. The dendrimer according to claim 1 represented by the following formula (IV): ##STR00254## or the pharmaceutically acceptable salts thereof, wherein ?, A, B, E, G, J, L, V, W.sup.1, W.sup.2, m are as defined previously or in formula (I), and D and D are independently selected from C1-C12 alkyl, C1-C12 haloalkyl, aryl, heteroaryl, (CH.sub.2CH.sub.2O).sub.aCH.sub.3, CH.sub.2(CH.sub.2CH.sub.2O).sub.aCH.sub.3, (CH.sub.2).sub.bNRR and CH.sub.2(CH.sub.2CH.sub.2O).sub.cCH.sub.2CH.sub.2CH.sub.2NRR, where a, b and c are, independently of one another, integers of between 1 and 12, and R and R are, independently of one another, selected from H, C1-C12 alkyl, C1-C12 haloalkyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl, methoxycarbonyl, tert-butylcarbonyl, p-toluenesulfonyl, methylsulfonyl, trifluoromethylsulfonyl, allyl, benzyl, trityl, ##STR00255## where Z.sup.1 is a single bond or a linear or branched hydrocarbon chain having 1 to 6 chain members, one or more chain members optionally being a heteroatom, and R.sup.1 and R.sup.2 are, independently of one another, selected from H, C1-C6 alkyl and M.sup.+, where M.sup.+ is a cation;

    17. The dendrimer according to claim 1, selected from: ##STR00256## ##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267##

    18. A method for preparing a dendrimer according to claim 1, comprising the following steps, in succession: (a) preparing an intermediate of the following formula: ##STR00268## or a pharmaceutically acceptable salt thereof, wherein ?, A, B and D are as defined in claim 1; (b) reacting the intermediate obtained in step (a) with P(E)X.sub.3, where E is O or S and X is a halogen; (c) reacting the product obtained in step (b) with a fragment comprising an intermediate chain and an end group.

    19. A method for preparing a dendrimer according to claim 1, comprising the following steps, in succession: (a) preparing a fragment comprising a generation chain, an intermediate chain and an end group of the following formula: ##STR00269## or a pharmaceutically acceptable salt thereof, wherein A, B, D, E, G, J, L, V, W.sup.1 and W.sup.2 are as defined in claim 1; (b) reacting the fragment obtained in step (a) with a halogenated central core ?.

    20. A pharmaceutical composition comprising at least one dendrimer according to claim 1 and a pharmaceutically acceptable excipient.

    21. A method of using the dendrimer according to claim 1 comprising providing the dendrimer to a subject as a medicament.

    22. (canceled)

    23. A method of using the pharmaceutical composition according to claim 20 comprising providing the pharmaceutical composition to a subject as a medicament.

    24. A method of treating or preventing an inflammatory disease comprising administering to a subject a therapeutically effective amount of the dendrimer according to claim 1.

    25. The method according to claim 24, wherein the inflammatory disease selected from chronic inflammatory diseases, autoimmune inflammatory diseases and pro-inflammatory and inflammatory conditions associated with a cancer.

    26. A method of treating or preventing an inflammatory disease comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition according to claim 20.

    27. The method according to claim 26, wherein the inflammatory disease selected from chronic inflammatory diseases, autoimmune inflammatory diseases and pro-inflammatory and inflammatory conditions associated with a cancer.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0400] FIG. 1 shows the structure of the dendrimer 1-G.sub.1-HCl (compound 1).

    [0401] FIG. 2 shows the structure of the dendrimer 1-G.sub.1-HTFA (compound 2).

    [0402] FIG. 3 shows the structure of the dendrimer 1-G.sub.2-HTFA (compound 3).

    [0403] FIG. 4 shows the structure of the dendrimer 1-G.sub.3-HTFA (compound 4).

    [0404] FIG. 5 shows the structure of the dendrimer 1-G.sub.4-HTFA (compound 5).

    [0405] FIG. 6 shows the structure of the dendrimer 3-G.sub.1(OMe) (compound 6).

    [0406] FIG. 7 shows the structure of the dendrimer 3-G.sub.1(OH) (compound 7).

    [0407] FIG. 8 shows the structure of the dendrimer 3-G.sub.1(ONa) (compound 8).

    [0408] FIG. 9 shows the structure of the dendrimer 4-G.sub.1(OMe) (compound 9).

    [0409] FIG. 10 shows the structure of the dendrimer 4-G.sub.1(OH) (compound 10).

    [0410] FIG. 11 shows the structure of the dendrimer 4-G.sub.1(ONa) (compound 11).

    [0411] FIG. 12 shows the structure of the dendrimer 5-G.sub.1(OMe) (compound 12).

    [0412] FIG. 13 shows the structure of the dendrimer 5-G.sub.1(OH) (compound 13).

    [0413] FIG. 14 shows the structure of the dendrimer 5-G.sub.1(ONa) (compound 14).

    [0414] FIG. 15 shows the structure of the dendrimer 11a-G.sub.1(NH-NAC (compound 15).

    [0415] FIG. 16 shows the structure of the dendrimer 11 b-G.sub.1(NH-NAC (compound 16).

    [0416] FIG. 17 shows the structure of the dendrimer 11c-G.sub.1(NH-NAC (compound 17).

    [0417] FIG. 18 shows the structure of the dendrimer 11a-G.sub.1(NH-NAC/PO.sub.3HNa) (compound 18).

    [0418] FIG. 19 shows the structure of the dendrimer 11 b-G.sub.1(NH-NAC/PO.sub.3HNa) (compound 19).

    [0419] FIG. 20 shows the structure of the dendrimer 11c-G.sub.1(NH-NAC/PO.sub.3HNa) (compound 20).

    [0420] FIG. 21 shows the structure of the dendrimer 12-G.sub.2-HTFA (compound 21).

    [0421] FIG. 22 shows the structure of the dendrimer 14-G.sub.2(OMe) (compound 22).

    [0422] FIG. 23 shows the .sup.31P-{.sup.1H} NMR spectra of the dendrimer ABP according to the prior art at pH=7.2 at 25? C. A: t=0, B: t=4 days, C: t=10 days, D: t=60 days, E: t=8 months.

    [0423] FIG. 24 shows the .sup.31P-{.sup.1H} NMR spectra of the compound 3-G1(ONa) according to the invention at pH=7.2 at 25? C. A: t=0, B: t=15 days, C: t=45 days, D: t=6 days, E: t=8 months.

    [0424] FIG. 25 shows the .sup.31P-{.sup.1H} NMR spectra of the dendrimer ABP according to the prior art at pH=5 at 25? C. A: t=0, B: t=5 days, C: t=10 days, D: t=30 days, E: t=90 days.

    [0425] FIG. 26 shows the .sup.31P-{.sup.1H} NMR spectra of the compound 3-G1(ONa) according to the invention at pH=5 at 25? C. A: t=0, B: t=5 days, C: t=15 days, D: t=90 days, E: t=240 days.

    [0426] FIG. 27 shows the .sup.31P-{.sup.1H} NMR spectra of the compound 4-G1(ONa) according to the invention at pH=7 at 25? C. A: t=0, B: t=5 days, C: t=15 days, D:t=90 days, E:t=120 days.

    [0427] FIG. 28 shows the .sup.31P-{.sup.1H} NMR spectra of the compound 5-G1(ONa) according to the invention at pH=7 at 25? C. A: t=0, B: t=5 days, C: t=15 days, D:t=90 days, E:t=120 days.

    [0428] FIG. 29 shows the .sup.31P-{.sup.1H} NMR spectra of the compound 5-G1(ONa) according to the invention at pH=4 at 25? C. A: t=0, B: t=5 days, C: t=15 days, D:t=90 days, E:t=120 days.

    [0429] FIG. 30 shows flow cytometric analysis of the morphology of monocytes cultured with the dendrimer 3-G.sub.1(ONa).

    EXAMPLES

    Chemical Synthesis

    [0430] All the temperatures are expressed in ? C. and all the reactions were carried out at ambient temperature (AT) unless indicated otherwise.

    [0431] The reactions were monitored using thin-layer chromatography (TLC) carried out on ready-to-use sheets of aluminum covered with a silica gel and a fluorescence indicator UV254 (Kieselgel? 60 F254 Merck, 0.2 mm thick) or equivalent, or by .sup.31P NMR.

    [0432] Preparatory column chromatographies were carried out by the silica gel chromatography method, using silica with a particle size of 63 to 200 ?m, by Sigma Aldrich.

    [0433] The NMR analyses were carried out on a 300 MHz, 400 MHz or 600 Mhz Bruker spectrometer. The spectra are recorded in solution in deuterated chloroform (CDCl.sub.3), in deuterated dichloromethane (CD.sub.2Cl.sub.2), in deuterated acetonitrile (CD.sub.3 CN), in deuterated methanol (CD.sub.3OD) or else in deuterated dimethyl sulfoxide (DMSO-d6). The chemical shifts (?) are given in ppm followed, for the proton spectra, by the multiplicity, where s, brs, d, t, q, dd, td, and m denote, respectively, singlets, broad singlets, doublets, triplets, quadruplets, doublets of doublets, triplets of doublets and multiplets (or incompletely resolved peaks). The multiplicities are followed, where appropriate, by the value of the coupling constants, denoted J and expressed in Hertz (Hz). All carbon (.sup.13C) and phosphorus (.sup.31P) NMR spectra were performed by removing the couplings with protons (.sup.13C-{.sup.1H} NMR and .sup.31P-{.sup.1H}) NMR).

    [0434] The solvents, reagents and starting materials were purchased from well-known chemicals suppliers such as Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, Sopachem and Polymer. The solvents, unless indicated otherwise, were purified by distillation before use. The reagents and the starting materials, unless indicated otherwise, were used without additional purifications.

    [0435] The following abbreviations were used: [0436] DCM: dichloromethane, [0437] DIPEA: diisopropylamine, [0438] Eq. or equiv.: equivalent, [0439] EtOAc: ethyl acetate, [0440] EtOH: ethanol, [0441] MeOH: methanol, [0442] NMR: nuclear magnetic resonance, [0443] AT: ambient temperature, [0444] TFA: trifluoroacetic acid, [0445] THF: tetrahydrofuran.

    Synthesis of Generation 1 to 5 Dendrimers

    [0446] Scheme 1 describes the reaction scheme of a first generation dendrimer.

    ##STR00133## ##STR00134## ##STR00135##

    [0447] Numbering Used for the NMR Assignment:

    ##STR00136##

    Synthesis of Compound 1-G.SUB.0 .from N.SUB.3.P.SUB.3.Cl.SUB.6 .(Macromolecules, 1981, 14, 1616-1622)

    [0448] ##STR00137##

    [0449] K.sub.2CO.sub.3 (14.3 g, 103.5 mmol) and 4-hydroxybenzaldehyde (4634 mg, 37.95 mmol) are added in succession to a solution of N.sub.3P.sub.3Cl.sub.6 (2000 mg, 5.75 mmol) in THF (200 mL) at ambient temperature. After 72 h with stirring at ambient temperature, the mixture is filtered then concentrated to dryness. The crude residue is washed 4 to 5 times in MeOH to give compound 1-G.sub.0 in the form of a white powder at a yield of 81%.

    [0450] .sup.1H NMR (300 MHz, CDCl.sub.3): ? (ppm) 9.83 (s, 6H, CHO), 7.74 (d, .sup.3J.sub.HH=8.6 Hz, 12H, C.sub.0.sup.3H), 7.12 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.2H).

    [0451] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sup.3): ? (ppm) 7.15 (s, P.sub.0).

    [0452] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3): ? (ppm) 190.47 (s, CHO), 154.44 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 133.74 (s, C.sub.0.sup.4), 131.38 (s, C.sub.0.sup.3), 121.21 (d, .sup.3J.sub.CP=2.5 Hz, C.sub.0.sup.2).

    Synthesis of Compound 1-G.SUB.0 .from 1-G.SUB.0

    [0453] ##STR00138##

    [0454] A solution of methylamine at 8 M in EtOH (1.3 mL, 10.45 mmol) is added to a solution of compound 1-G.sub.0 (500 mg, 0.580 mmol) in THF (50 mL) at ambient temperature. After stirring overnight at ambient temperature, the mixture is concentrated to dryness to give the dendrimer 1-G.sub.0 in the form of a white powder.

    [0455] .sup.1H NMR (300 MHz, CD.sub.3CN): ? (ppm) 8.24 (d, .sup.4J.sub.HH=1.7 Hz, 6H, CH?N), 7.55 (d, .sup.3J.sub.HH=8.6 Hz, 12H, C.sub.0.sup.3H), 6.99 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.2H), 3.50 (s, 18H, NCH.sub.3)

    [0456] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.3CN): ? (ppm) 8.66 (s, P.sub.0).

    [0457] .sup.13C-{.sup.1H}NMR (75 MHz, CD.sub.3CN): ? (ppm) 160.80 (s, C?N), 151.57 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 133.94 (s, C.sub.0.sup.4) 129.13 (C.sub.0.sup.3), 120.66 (dd, .sup.3J.sub.CP=3.2 Hz, .sup.5J.sub.CP=1.8 Hz, C.sub.0.sup.2), 47.29 (s, CH.sub.3).

    Synthesis of Compound 1-AB-Boc

    [0458] ##STR00139##

    [0459] Methylamine (8 M in EtOH) (3.07 mL, 24.56 mmol) is added to a solution of 4-hydroxybenzaldehyde (1000 mg, 8.188 mmol) in THF (50 mL). After stirring overnight at ambient temperature, the reaction is terminated. Compound 1 is not isolated and is directly used thereafter.

    [0460] .sup.1H NMR (400 MHz, CD.sub.3OD): ? (ppm) 8.16 (s, 1H, CH?N), 7.52 (d, J=8.7 Hz, 2H, C.sub.0.sup.3H), 6.77 (d, J=8.6 Hz, 2H, C.sub.0.sup.2H), 2.40 (s, 3H, CH.sub.3).

    ##STR00140##

    [0461] NaBH.sub.4 (371 mg, 9.81 mmol) is subsequently added to the reaction medium. After 12 h of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The crude residue is then dissolved in a solution of HCl (1 M in MeOH) (29.43 mL, 29.43 mmol). After 3 h of stirring at ambient temperature, the solution is filtered then concentrated under reduced pressure to give a white powder. The powder is washed with 3?50 mL of CH.sub.2Cl.sub.2 to give the corresponding amine hydrochloride in the form of a white powder at a yield of 98%.

    [0462] .sup.1H NMR (300 MHz, CD.sub.3OD): ? (ppm) 7.35 (d, .sup.3J.sub.HH=8.7 Hz, 2H, C.sub.0.sup.3H), 6.87 (d, .sup.3J.sub.HH=8.7 Hz, 2H, C.sub.0.sup.2H), 4.10 (s, 2H, CH.sub.2), 2.69 (s, 3H, CH.sub.3).

    ##STR00141##

    [0463] Boc.sub.2O (2386 mg, 10.93 mmol) is added to a solution of the previously obtained amine hydrochloride (2000 mg, 11.51 mmol) in CH.sub.2Cl.sub.2 (200 mL) in the presence of DIPEA (1.942 mL, 10.93 mmol). After 72 h at ambient temperature, the mixture is washed directly 1 time with 100 mL of distilled water at pH=5. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The powder obtained is subsequently washed with 3?50 mL of hexane to give the compound 1-AB-Boc in the form of a white powder at a yield of 75%.

    [0464] .sup.1H NMR (300 MHz, CDCl.sub.3): ? (ppm) 7.07 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.3H), 6.83 (d, .sup.3J.sub.HH=7.6 Hz, 2H, C.sub.0.sup.2H), 4.35 (s, 2H, CH.sub.2), 2.81 (s, 3H, CH.sub.3), 1.51 (s, 9H, Boc).

    [0465] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3: ? (ppm) 156.30 (s, NC(O)OtButyl), 155.68 (s, C.sub.0.sup.1), 129.12 (s, C.sub.0.sup.4), 128.73 (s, C.sub.0.sup.3), 115.51 (s, C.sub.0.sup.2), 80.21 (s, OC-tButyl), 52.11 (CH.sub.2 NBoc), 51.32 (CH.sub.2NBoc), 33.78 (s, NCH.sub.3), 28.51 (s, C(CH.sub.3).sub.3).

    Synthesis of Compound 1-AB.SUB.2.-CHO (Mitjaville J. et al., J. Am. Chem. Soc., 1994, 116, 5007-5008)

    [0466] ##STR00142##

    [0467] A solution of 4-hydroxybenzaldehyde (2000 mg, 16.38 mmol) with Et.sub.3N (4.566 mL, 32.76 mmol) in THF (50 mL) is added dropwise over a duration of 30 min to a solution of PSCl.sub.3 (0.810 mL, 7.99 mmol), in THF (200 mL) with molecular sieve, cooled to ?78? C. After addition, the mixture slowly rises to ambient temperature. After 12 h of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently purified using silica gel chromatography with a 5/95.fwdarw.10/90 EtOAc/Hexane gradient, to give compound 1-AB.sub.2-CHO in the form of an orange oil at a yield of 76%.

    [0468] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3): ? (ppm) 55.86 (s, P.sub.0).

    Synthesis of Compound 1-AB.SUB.2.-Boc

    [0469] ##STR00143##

    [0470] A solution of compound AB-Boc (2000 mg, 3.50 mmol) with Et.sub.3N (1.025 mL, 7.36 mmol) in CH.sub.2Cl.sub.2 (30 to 50 mL) is added dropwise over a duration of 30 min to a solution of PSCl.sub.3 (0.173 mL, 1.70 mmol) in CH.sub.2Cl.sub.2 (200 mL), with molecular sieve, cooled to ?78? C. After addition, the reaction mixture rises slowly to ambient temperature. After 72 h of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently purified using silica gel chromatography with a 5/95.fwdarw.10/90 EtOAc/Hexane gradient, to give compound 1-AB.sub.2-Boc in the form of a transparent oil at a yield of 84%.

    [0471] .sup.1H NMR (400 MHz, CDCl.sub.3): ? (ppm) 7.28 (s, 4H, CH-arom), 4.44 (s, 2H, CH.sub.2), 2.85 (s, 3H, CH.sub.3), 1.49 (s, 9H, Boc).

    [0472] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 58.82 (s, P.sub.0).

    [0473] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3): ? (ppm) 155.85 (brs, NC(O)OtButyl), 149.26 (d, .sup.2J.sub.CP=10.0 Hz, C.sub.0.sup.1), 136.53 (s, C.sub.0.sup.4), 128.73 (brs, C.sub.0.sup.3), 121.30 (d, .sup.3J.sub.CP=5.2 Hz, C.sub.0.sup.2), 79.87 (s, OC-tButyl), 52.00 (brs, CH.sub.2NBoc), 51.28 (brs, CH.sub.2NBoc), 34.07 (s, NCH.sub.3), 28.43 (s, C (CH.sub.3).sub.3).

    Synthesis of Compound 1-G.SUB.0.-Boc from N.SUB.3.P.SUB.3.Cl.SUB.6

    [0474] ##STR00144##

    [0475] Cs.sub.2CO.sub.3 (6.30 mmol) and compound 1-AB-Boc (3.15 mmol) are added in succession to a solution of hexachlorocyclotrisphophazene (0.5 mmol) in THF (50 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is subsequently purified using silica gel chromatography with a CH.sub.2Cl.sub.2/EtOAc) mixture to give dendrimer 1-G.sub.0-Boc in the form of a white powder at a yield of 86%.

    [0476] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 8.2 (s, P.sub.0).

    Synthesis of Compound 1-G.SUB.0.-HCl from 1-G.SUB.0

    [0477] ##STR00145##

    [0478] NaBH.sub.4 (201 mg, 5.32 mmol) is added to a solution of dendrimer 1-G.sub.0 (500 mg, 0.53 mmol) in a THF/MeOH (25/5) mL mixture. After stirring overnight at ambient temperature, the mixture is concentrated to dryness. The crude residue is diluted in 200 mL of DCM then washed once with 50 mL distilled water. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product is then dissolved in MeOH (30 mL) to which 9.5 mL of HCl (1 M in MeOH) is added. After 2 h of stirring at ambient temperature, the solution is filtered then concentrated under reduced pressure. The residue is washed 3 times with 25 mL CH.sub.2Cl.sub.2 to give the product 1-G.sub.0-HCl (protonated HCl form) in the form of a white powder.

    [0479] .sup.1H NMR (400 MHz, CD.sub.3OD): ? (ppm) 7.54 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H), 7.05 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2H), 4.27 (s, 12H, CH.sub.2NH), 2.75 (s, 18H, NCH.sub.3).

    [0480] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3OD): ? (ppm) 8.29 (s, P.sub.0).

    [0481] .sup.13C-{.sup.1H} NMR (101 MHz, CD.sub.3OD): ? (ppm) 151.07 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 131.46 (s, C.sub.0.sup.3), 128.71 (s, C.sub.0.sup.4), 121.12 (dd, .sup.3J=3.2, .sup.5J=1.7 Hz, (s, C.sub.0.sup.2), 51.30 (s, CH.sub.2NH), 31.88 (s, NCH.sub.3).

    Synthesis of Compound 1-G.SUB.0.-HTFA from 1-G.SUB.0.-Boc

    [0482] ##STR00146##

    [0483] Compound 1-G.sub.0-HTFA (protonated TFA form) is obtained by dissolving compound 1-G.sub.0-Boc (300 mg) in 10 mL of a CH.sub.2Cl.sub.2/TFA (50/50) mixture for 60 minutes at ambient temperature then evaporating the reaction mixture to dryness.

    [0484] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3OD): ? (ppm) 8.3 (s, P.sub.0).

    Synthesis of Compound 1-G.SUB.0 .from 1-G.SUB.1.-HTFA or 1-G.SUB.1.-HCl

    [0485] ##STR00147##

    [0486] Compound 1-G.sub.0-HTFA or 1-G.sub.0-HCl (300 mg) is dissolved in 25 mL of distilled water to which 25 mL of a solution of NaOH (2M) is added. The aqueous phase is subsequently extracted 3 times with 200 mL of CH.sub.2Cl.sub.2. The organic phase is subsequently dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give dendrimer 1-G.sub.0 in the form of a transparent oil at a yield of 80%.

    [0487] .sup.1H NMR (400 MHz, CDCl.sub.3): ? (ppm) 7.12 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H), 6.91 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2H), 3.69 (s, 12H, CH.sub.2NH), 2.43 (s, 18H, NCH.sub.3).

    [0488] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 8.71 (s, P.sub.0).

    [0489] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3): ? (ppm) 149.55 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 136.70 (s, C.sub.0.sup.3), 128.99 (s, C.sub.0.sup.4), 120.82 (dd, .sup.3J=3.4, .sup.5J=1.7 Hz, (s, C.sub.0.sup.2), 55.43 (s, CH.sub.2NH), 36.06 (s, NCH.sub.3).

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.0

    [0490] ##STR00148##

    [0491] A solution of dendrimer 1-G.sub.0 (800 mg, 0.85 mmol) is added dropwise to a solution of PSCl.sub.3 (3.109 mL, 30.60 mmol) in CH.sub.2Cl.sub.2 (100 mL) in the presence of Et.sub.3N (0.740 mL, 5.31 mmol) in CH.sub.2Cl.sub.2 (25 mL) over a duration of 30 min. After 3 h of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of CH.sub.2Cl.sub.2 then filtered over silica gel to give dendrimer 1-G1 in the form of a white powder at a yield of 82%.

    [0492] .sup.1H NMR (300 MHz, CDCl.sub.3): ? (ppm) 7.22 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H), 6.99 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2H), 4.60 (d, .sup.3J.sub.HP=15.1 Hz, 12H, CH.sub.2NH), 2.82 (d, .sup.3J.sub.HP=16.2 Hz, 18H, NCH.sub.3).

    [0493] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3): ? (ppm) 64.12 (s, P.sub.1, 8.35 (s, P.sub.0).

    [0494] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3): ? (ppm) 150.26 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 132.73 (d, .sup.3J.sub.CP=6.5 Hz, C.sub.0.sup.4), 129.17 (s, C.sub.0.sup.3), 121.29-121.15 (m, C.sub.0.sup.2), 54.18 (d, .sup.2J.sub.CP=5.5 Hz, CH.sub.2NH), 35.11 (d, .sup.2J.sub.CP=2.5 Hz, NCH.sub.3).

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.0.-HTFA or 1-G.SUB.0.-HCl

    [0495] ##STR00149##

    [0496] PSCl.sub.3 (5 to 10 equivalents per terminal protonated amine, i.e. 5*0.05*2.sup.ny to 10*0.05*2.sup.ny mmol) is added very quickly to a solution of compound 1-G.sub.0-HTFA or 1-G.sub.n-HCl (0.05 mmol) in CH.sub.2Cl.sub.2 (25 mL) with a base, preferentially organic and non-nucleophilic, such as DIPEA (2 to 3 equivalents per terminal protonated amine, i.e. 2*0.05*2.sup.ny to 3*0.05*2.sup.ny mmol) cooled to ?78? C. The mixture is slowly brought to ambient temperature. After stirring overnight at ambient temperature, the reaction mixture is evaporated to dryness under reduced pressure. The crude residue is diluted with 200 mL of CH.sub.2Cl.sub.2 and filtered over silica gel. The solution is subsequently dried over MgSO.sub.4 and concentrated under reduced pressure. The residue obtained is washed 3 times with a CHCl.sub.3/alkane ( 1/10) mixture to give the product G.sub.1 in the form of a white powder.

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.1

    [0497] ##STR00150##

    [0498] Cs.sub.2CO.sub.3 (1341 mg, 4.11 mmol) and 4-hydroxybenzaldehyde (314.2 mg, 2.57 mmol) are added in succession to a solution of dendrimer 1-G.sub.1 (300 mg, 0.171 mmol) in THF (30 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The product is subsequently purified using silica gel chromatography (50/50 to 60/40 EtOAc/Hexane gradient), to give dendrimer 1-G1 in the form of a white powder at a yield of 73%.

    [0499] .sup.1H NMR (400 MHz, CDCl.sub.3): ? (ppm) 9.96 (s, 12H, CHO), 7.88 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.33 (d, .sup.3J.sub.HH=8.3 Hz, 24H, C.sub.1.sup.2H), 7.18 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H), 6.97 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.2H), 4.49 (d, .sup.3J.sub.HP=13.4 Hz, 12H, CH.sub.2NH), 2.83 (d, .sup.3J.sub.HP=10.6 Hz, 18H, NCH.sub.3).

    [0500] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 66.34 (s, P.sub.1), 8.35 (s, P.sub.0).

    [0501] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3): ? (ppm) 190.65 (s, CHO), 155.31 (d, .sup.2J.sub.CP=7.3 Hz, C.sub.1.sup.1), 150.14 (dd, .sup.2J.sub.CP=5.1 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 133.66 (d, .sup.3J.sub.CP=4.4 Hz, C.sub.0.sup.4), 133.57 (d, .sup.5J.sub.CP=1.3 Hz, C.sub.1.sup.4), 131.48 (s, C.sub.1.sup.3), 129.42 (s, C.sub.0.sup.3), 121.63 (d, .sup.3J.sub.CP=5.0 Hz, C.sub.1.sup.2), 121.01 (m, C.sub.0.sup.2), 53.67 (d, .sup.2J.sub.CP=7.8 Hz, CH.sub.2NH), 33.72 (d, .sup.2J.sub.CP=1.5 Hz, NCH.sub.3).

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.0

    [0502] ##STR00151##

    [0503] Compound 1-AB.sub.2-CHO (0.63 mmol) is added to a solution of compound 1-G.sub.0 (0.1 mmol) in THF (30 mL) in the presence of DIPEA (1.5 mmol). After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently purified by silica gel chromatography to give compound 1-G.sub.1 in the form of a white powder.

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.0.-HTFA or 1-G.SUB.0.-HCl

    [0504] ##STR00152##

    [0505] Compound 1-AB.sub.2-CHO (0.63 mmol) is added to a solution of compound 1-G.sub.0-TFA or 1-G.sub.0-HCl (0.1 mmol) in THF (30 mL) in the presence of DIPEA (1.8 mmol). After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently purified by silica gel chromatography to give compound 1-G.sub.1 in the form of a white powder.

    Synthesis of Compound 1-G.SUB.1 .from 1-G.SUB.1

    [0506] ##STR00153##

    [0507] An 8M solution of methylamine in EtOH (320 ?L, 2.59 mmol) is added to a solution of compound 1-G.sub.1 (200 mg, 0.072 mmol) in THF (20 mL). After stirring overnight at ambient temperature, the mixture is concentrated to dryness under reduced pressure to give the dendrimer 1-G.sub.1 in the form of a white powder. The yield is quantitative.

    [0508] .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.12): ? (ppm) 8.25 (d, .sup.4J.sub.HH=1.6 Hz, 12H, CH?N), 7.71 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.32-7.10 (m, 36H, C.sub.1.sup.2H, C.sub.0.sup.3H), 6.96 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 4.48 (d, .sup.3J.sub.HP=13.0 Hz, 12H, CH.sub.2N.sub.0H), 3.48 (d, .sup.4J.sub.HH=1.5 Hz, 36H, C?N.sub.1CH.sub.3), 2.80 (d, .sup.3J.sub.HP=10.7 Hz, 18H, N.sub.0CH.sub.3).

    [0509] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.2Cl.sub.12): ? (ppm) 67.60 (s, P.sup.1), 8.59 (s, P.sub.0).

    Synthesis of Dendrimer 1-G.SUB.1.-HCl from 1-G.SUB.1

    [0510] ##STR00154##

    [0511] A 1 M solution of BH.sub.3.Math.THF in THF (792 ?l, 0.792 mmol) is added to a solution of compound 1-G1 (155 mg, 0.053 mmol) in THF (20 mL). After stirring overnight at ambient temperature, 4 mL of MeOH are added. After stirring for one hour, the reaction mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently dissolved in a 1 M solution of HCl in MeOH (1908 ?l, 1.908 mmol). The solution is subsequently filtered then concentrated to dryness under reduced pressure. The powder obtained is washed 3 times with 10 mL of CH.sub.2Cl.sub.2 to give compound 1-G.sub.1-HCl (protonated form) in the form of a white powder at a yield of 90%.

    [0512] .sup.1H NMR (300 MHz, CD.sub.3OD): ? (ppm) 7.59 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.28 (m, 36H, C.sub.1.sup.2H, C.sub.0.sup.3H), 6.92 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 4.51 (d, .sup.3J.sub.HP=14.0 Hz, 12H, CH.sub.2N.sub.0H), 4.21 (s, 24H, CH.sub.2N.sub.1H), 2.82 (d, .sup.3J.sub.HP=10.5 Hz, 18H, N.sub.0CH.sub.3), 2.73 (s, 36H, N.sub.1CH.sub.3).

    [0513] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.3OD): ? (ppm) 67.97 (s, P.sub.1), 9.07 (s, P.sub.0).

    [0514] .sup.13C NMR (75 MHz, CD.sub.3OD): ? (ppm) 151.81 (d, .sup.2J.sub.CP=7.4 Hz, C.sub.1.sup.1), 149.79 (dd, .sup.2J.sub.CP=4.4 Hz, .sup.4J.sub.CP=3.0 Hz, C.sub.0.sup.1), 134.33 (d, .sup.3J.sub.CP=4.5 Hz, C.sub.0.sup.4), 131.35 (s, C.sub.1.sup.3), 129.26 (s, C.sub.0.sup.3), 128.33 (d, .sup.5J.sub.CP=1.2 Hz, C.sub.1.sup.4), 121.61 (d, .sup.3J.sub.CP=4.5 Hz, C.sub.1.sup.2), 120.65 (s, C.sub.0.sup.2), 53.01 (d, .sup.2J.sub.CP=6.9 Hz, CH.sub.2N.sub.0H), 51.46 (s, CH.sub.2N.sub.1H), 33.00 (d, .sup.2J.sub.CP=1.6 Hz, N.sub.0CH.sub.3), 31.85 (s, N.sub.1CH.sub.3).

    [0515] The structure of dendrimer 1-G.sub.1-HCl is represented in [FIG. 1].

    Synthesis of Compound 1-G.SUB.1.-Boc from 1-G.SUB.1

    [0516] ##STR00155##

    [0517] Cs.sub.2CO.sub.3 (5570 mg, 17.14 mmol) and compound 1-AB-Boc (2035 mg, 8.57 mmol) are added in succession to a solution of compound 1-G.sub.1 (1000 mg, 0.571 mmol) in THF (50 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is subsequently purified using silica gel chromatography with a CH.sub.2Cl.sub.2/EtOAc) mixture to give dendrimer 1-G.sub.1-Boc in the form of a white powder at a yield of 76%.

    [0518] .sup.1H NMR (300 MHz, CDCl.sub.3): ? (ppm) 7.26-7.11 (m, 60H, C.sub.1.sup.3H, C.sub.1.sup.2H, C.sub.0.sup.3H), 6.94 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 4.47 (d, .sup.3J.sub.HP=12.6 Hz, 12H, CH.sub.2N.sub.0H), 4.38 (s, 24H, CH.sub.2N.sub.1H), 2.87-2.71 (m, 54H, N.sub.0CH.sub.3, N.sub.1CH.sub.3), 1.47 (s, 108H, Boc).

    [0519] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3): ? (ppm) 68.11 (s, P.sub.1, 8.46 (s, P.sub.0).

    [0520] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3): ? (ppm) 156.07 (s, CO), 155.66 (s, CO), 150.22-149.91 (m, C.sub.1.sup.1, C.sub.0.sup.1), 135.02 (s, C.sub.1.sup.4), 134.06 (d, .sup.3J.sub.CP=4.4 Hz, C.sub.0.sup.4), 129.30 (s, C.sub.0.sup.3), 128.63 (brs, C.sub.1.sup.3), 121.09 (d, .sup.3J.sub.CP=4.8 Hz, C.sub.1.sup.2), 120.95 (s, C.sub.0.sup.2), 79.72 (s, OC-tButyl), 53.56 (d, .sup.2J.sub.CP=7.1 Hz, CH.sub.2N.sub.0H), 51.64 (d, J=56.7 Hz, CH.sub.2N.sub.1Boc), 33.93 (s, N.sub.1CH.sub.3), 33.65 (d, .sup.2J.sub.CP=1.7 Hz, N.sub.0CH.sub.3), 28.45 (s, C(CH.sub.3).sub.3).

    Synthesis of Compound 1-G.SUB.1.-Boc from 1-G.SUB.0.-HTFA or 1-G.SUB.0..-HCl

    [0521] ##STR00156##

    [0522] Compound 1-AB.sub.2-Boc (1.26 mmol) is added to a solution of compound 1-G.sub.1 (0.1 mmol) in THF (30 mL) in the presence of DIPEA (3 mmol). After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently purified on a silica gel column to give compound 1-G.sub.1 in the form of a white powder.

    Synthesis of Compound 1-G.SUB.1.-Boc from 1-G.SUB.0

    [0523] ##STR00157##

    [0524] Compound 1-AB.sub.2-Boc (1.26 mmol) is added to a solution of compound 1-G.sub.1-TFA or 1-G.sub.1-HCl (0.1 mmol) in THF (30 mL) in the presence of DIPEA (3.6 mmol). After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently purified on a silica gel column to give compound 1-G.sub.1 in the form of a white powder.

    Synthesis of Dendrimer 1-G.SUB.1.-HTFA from 1-G.SUB.1.-Boc

    [0525] ##STR00158##

    [0526] Compound 1-G.sub.nBoc (200 mg) is dissolved in a CH.sub.2Cl.sub.2/trifluoroacetic acid 70/30 mixture (30 mL). After 30 min of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is subsequently co-evaporated 5 times with 3 mL of CH.sub.2Cl.sub.2 to give dendrimer 1-G.sub.n-HTFA in the form of a white powder.

    [0527] .sup.1H NMR (400 MHz, CD.sub.3CN) ? (ppm): 2.64 (s), 2.77 (d, J=10.8 Hz), 4.11 (s), 4.47 (d, J=13.4 Hz), 6.93 (d, J=8.4 Hz), 7.23 (d, J=9.7 Hz), 7.47 (d, J=8.6 Hz).

    [0528] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 9.09 (s, P0), 67.80 (s, P1).

    [0529] The structure of dendrimer 1-G.sub.1-HTFA is represented in [FIG. 2].

    Synthesis of Compound 1-G.SUB.2 .from 1-G.SUB.1.-HTFA or 1-G.SUB.1.-HCl

    [0530] ##STR00159##

    [0531] PSCl.sub.3 (337 ?l, 3.32 mmol) is added very quickly to a solution of 1-G.sub.1-HTFA (200 mg, 0.046 mmol) or 1-G.sub.1-HCl in CH.sub.2Cl.sub.2 (25 mL) with DIPEA (246 ?l, 1.386 mmol) cooled to ?78? C. After addition, the mixture slowly rises to ambient temperature. After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue obtained is diluted with 200 mL of CH.sub.2Cl.sub.2 and filtered over silica gel. The solution is subsequently dried with MgSO.sub.4 and concentrated under reduced pressure. The residue obtained is subsequently washed 3 times with a CHCl.sub.3/Pentane ( 1/10) mixture to give the product 1-G.sub.2 in the form of a white powder. The yield is 73%.

    [0532] .sup.1H NMR (500 MHz, CDCl.sub.3): ? (ppm) 7.33 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.26-7.11 (m, 36H, C.sub.0.sup.3H, C.sub.1.sup.2 H), 6.93 (d, .sup.3J.sub.HH=8.4 Hz, 12H), 4.60 (d, .sup.3J.sub.HP=14.9 Hz, 24H, CH.sub.2N.sub.1H), 4.50 (d, .sup.3J.sub.HP=12.8 Hz, 12H, CH.sub.2N.sub.0H), 2.92-2.77 (m, 54H, N.sub.1CH.sub.3, N.sub.0CH.sub.3).

    [0533] .sup.31P-{.sup.1H} NMR (202 MHz, CDCl.sub.3): ? (ppm) 67.86 (s, P.sub.1), 63.95 (s, P.sub.2), 8.49 (s, P.sub.0).

    [0534] .sup.13C-{.sup.1H} NMR (126 MHz, CDCl.sub.3): ? (ppm) 150.68 (d, .sup.2J.sub.CP=7.5 Hz, C.sub.1.sup.1), 150.02 (dd, .sup.2J.sub.CP=5.2 Hz, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1), 133.99 (d, .sup.3J.sub.CP=4.6 Hz, C.sub.0.sup.4), 132.73 (d, .sup.3J.sub.CP=6.6 Hz, C.sub.1.sup.4), 129.33 (s, C.sub.1.sup.3, C.sub.0.sup.3), 121.41 (d, .sup.3J.sub.CP=4.8 Hz, s, C.sub.1.sup.2), 120.97 (s, C.sub.0.sup.2), 54.21 (d, .sup.2J.sub.CP=5.3 Hz, CH.sub.2N.sub.1H), 53.64 (d, .sup.2J.sub.CP=7.4 Hz, CH.sub.2N.sub.0H), 35.15 (s, N.sub.1CH.sub.3), 33.74 (d, N.sub.0CH.sub.3).

    Synthesis of Compound 1-G.SUB.2 .from 1-G.SUB.1.-HTFA or 1-G.SUB.1.-HCl

    [0535] ##STR00160##

    [0536] Compound 1-AB.sub.2-CHO (1.26 mmol) is added to a solution of compound 1-G.sub.1-HTFA or 1-G.sub.1-HCl (0.1 mmol) in THF (30 mL) in the presence of DIPEA (3.6 mmol). After stirring overnight at ambient temperature, the mixture is evaporated to dryness under reduced pressure. The crude residue is subsequently purified on a silica gel column to give compound 1-G.sub.2 in the form of a white powder.

    [0537] .sup.1H NMR (400 MHz, CDCl.sub.3): ? (ppm) 9.93 (s, 12H), 9.94 (s, 12H), 7.87 (dd, J=8.5, 2.1 Hz, 48H), 7.34 (d, J=8.5 Hz, 48H), 7.26 (s, 24H), 7.19 (d, J=8.5 Hz, 12H), 7.11 (d, J=8.3 Hz, 24H), 6.95 (d, J=8.4 Hz, 12H), 4.54-4.44 (m, 36H), 2.86 (d, J=10.8 Hz, 36H), 2.78 (d, J=10.6 Hz, 18H).

    [0538] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 67.91 (s, P.sub.1), 66.33 (s, P.sub.2), 8.43 (s, P.sub.0).

    Synthesis of Compound 1-G.SUB.2 .from 1-G.SUB.2

    [0539] ##STR00161##

    [0540] Cs.sub.2CO.sub.3 (7.2 mmol) and 4-hydroxybenzaldehyde (2.5 mmol) are added in succession to a solution of dendrimer 1-G.sub.2 (0.15 mmol) in THF (30 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The product is subsequently purified using a silica gel chromatography column (50/50 to 60/40 EtOAc/Hexane gradient), to give dendrimer 1-G.sub.2 in the form of a white powder at a yield of 73%.

    [0541] Scheme 2 describes the reaction scheme of generations 2 to 5 dendrimers from a 1st generation dendrimer.

    ##STR00162## ##STR00163##

    General Procedure for Synthesis of Compounds 1-G.SUB.n.-Boc from 1-G.SUB.n.-1-HTFA with Synthon 1-AB.SUB.2.-Boc

    [0542] Compound AB.sub.2-Boc (n=1, 0.633 mmol, n=2, 1.265 mmol, n=3, 2.531 mmol, n=4, 5.062 mmol, n=5, 10.13 mmol) is added to a solution of 200 mg of the trifluoroacetic acid salt of dendrimer 1-G.sub.(n-1)-HTFA in CH.sub.2Cl.sub.2 (50 to 100 mL) with Et.sub.3N (n=1, 0.696 mmol, n=2, 1.392 mmol, n=3, 2.784 mmol, n=4, 5.569 mmol, n=5, 11.14 mmol). After stirring overnight at ambient temperature, the mixture is concentrated to dryness. The yields are between 50 and 90%.

    [0543] For n=1, 2 and 3, the crude residue is filtered over silica gel with an EtOAc/CH.sub.2Cl.sub.2 eluent gradient (5/95 to 30/70) to give compound 1-G.sub.n-Boc in oil form.

    [0544] For n=4, 5, the crude residue is washed 2 times with 10 mL of acetonitrile to give compound 1-G.sub.n-Boc in powder form.

    [0545] Characterization of 1-G.sub.2-Boc:

    ##STR00164##

    [0546] .sup.1H NMR (600 MHz, CD.sub.2Cl.sub.2): ? (ppm) 7.40-6.91 (m, 168H, CH-arom), 4.63-4.47 (d, .sup.3J.sub.HP=12.6 Hz, 36H, CH.sub.2N.sub.0H, CH.sub.2N.sub.1H), 4.40 (s, 48H, CH.sub.2N.sub.2H), 3.14-2.84 (m, 54H, N.sub.0CH.sub.3, N.sub.1CH.sub.3), 2.81 (s, 72H, N.sub.2CH.sub.3), 1.47 (brs, 216H, Boc).

    [0547] .sup.31P-{.sup.1H} NMR (243 MHz, CD.sub.2Cl.sub.2): ? (ppm) 68.38 (s, P.sub.2), 68.03 (s, P.sub.1), 8.39 (s, P.sub.0).

    [0548] .sup.13C-{.sup.1H} NMR (151 MHz, CD.sub.2Cl.sub.12): ? (ppm) 155.59 (d, NC(O)OtButyl), 150.43 (m, C.sub.1.sup.1, C.sub.0.sup.1), 150.06 (d, .sup.3J.sub.CP=7.5 Hz, C.sub.2.sup.1), 135.37 (s, C.sub.2.sup.4), 134.28 (s, C.sub.0.sup.4, C.sub.1.sup.4), 129.41 (m, C.sub.0.sup.3, C.sub.1.sup.3) 128.56 (d, C.sub.2.sup.3), 120.7-121.07 (m, C.sub.0.sup.2, C.sub.1.sup.2, C.sub.2.sup.2), 79.34 (s, OC-tButyl), 51.57 (d, CH.sub.2N.sub.2), 33.81 (s, N.sub.2CH.sub.3), 33.64 (s, N.sub.1CH.sub.3), 33.58 (s, N.sub.0CH.sub.3), 28.14 (s, C(CH.sub.3).sub.3).

    Characterization of 1-G.SUB.3.-Boc

    [0549] ##STR00165##

    [0550] .sup.1H NMR (600 MHz, CD.sub.2Cl.sub.2): ? (ppm) 7.41-6.97 (m, 10H, CH-arom), 4.49-4.65 (m, 10H, CH.sub.2N.sub.0H, CH.sub.2N.sub.1H, CH.sub.2N.sub.2H), 4.41 (s, 11H, CH.sub.2N.sub.3H), 3.01-2.88 (m, 1H, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3), 2.82 (s, 18H, N.sub.3CH.sub.3), 1.49 (d, 50H, Boc).

    [0551] .sup.31P-{.sup.1H} NMR (243 MHz, CD.sub.2Cl.sub.12): ? (ppm) 68.42 (s, P.sub.3), 68.14 (m, P.sub.1, P.sub.2), 8.28 (s, P.sub.0).

    [0552] .sup.13C-{.sup.1H} NMR (151 MHz, CD.sub.2Cl.sub.12): ? (ppm) 155.64 (d, NC(O)OtButyl), 150.50 (m, C.sub.1.sup.1, C.sub.0.sup.1, C.sub.2.sup.1), 150.11 (m, C.sub.3.sup.1) 135.41 (s, C.sub.3.sup.4), 134.30 (s, C.sub.0.sup.4, C.sub.1.sup.4, C.sub.2.sup.4), 129.45 (s, C.sub.0, C.sub.1.sup.3, C.sub.2.sup.3), 128.61 (s, C.sub.3.sup.3), 121.40-120.71 (m, C.sub.0.sup.2, C.sub.1.sup.2, C.sub.2.sup.2, C.sub.3.sup.2), 79.39 (s, OC-tButyl), 51.72-51.62 (m, CH.sub.2N), 33.86-33.61 (m, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3, N.sub.3CH.sub.3), 28.19 (s, C(CH.sub.3).sub.3).

    Characterization of 1-G.SUB.4.-Boc

    [0553] ##STR00166##

    [0554] .sup.1H NMR (400 MHz, CDCl.sub.3): ? (ppm) 7.40-7.04 (m, 744H, CH-arom), 4.51-4.28 (m, 372H, CH.sub.2N.sub.0, CH.sub.2N.sub.1, CH.sub.2N.sub.2, CH.sub.2N.sub.3, CH.sub.2N.sub.4), 3.03-2.68 (m, 558H, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3, N.sub.3CH.sub.3, N.sub.4CH.sub.3), 1.46 (s, 864H, Boc).

    [0555] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 68.16 (s, P.sub.4), 67.94 (m, P.sub.1 P.sub.2,P.sub.3), 7.85 (s, P.sub.0).

    [0556] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3): ? (ppm) 155.84 (d, NC(O)OtButyl), 150.62-150.27 (m, C.sub.1.sup.1, C.sub.0.sup.1, C.sub.2.sup.1, C.sub.3.sup.1), 150.09 (d, .sup.2J.sub.CP=7.5 Hz, C.sub.4.sup.1), 135.00 (s, C.sub.4.sup.4), 134.30 (d, .sup.3J.sub.CP=3.7 Hz, C.sub.0.sup.4, C.sub.1.sup.4, C.sub.2.sup.4, C.sub.3.sup.4), 129.47 (m, C.sub.0.sup.3, C.sub.1.sup.3, C.sub.2.sup.3, C.sub.3.sup.3), 128.63 (m, C.sub.4.sup.3), 121.11 (d, .sup.3J.sub.CP=4.3 Hz, C.sub.0.sup.2, C.sub.1.sup.2, C.sub.2.sup.2, C.sub.3.sup.2, C.sub.4.sup.2), 79.70 (s, OC-tButyl), 53.64-53.58 (m, CH.sub.2N.sub.1, CH.sub.2N.sub.2, CH.sub.2N.sub.3) 52.31-50.86 (m, CH.sub.2N.sub.4) 33.94-33.75 (m, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3, N.sub.3CH.sub.3, N.sub.3CH.sub.3), 28.46 (s, C(CH.sub.3).sub.3).

    Characterization of 1-G.SUB.5.-Boc

    [0557] ##STR00167##

    [0558] .sup.1H NMR (300 MHz, CDCl.sub.3): ? (ppm) 7.45-6.92 (m, 1512H, CH-arom), 4.43 (m, 756H, CH.sub.2N.sub.0, CH.sub.2N.sub.1, CH.sub.2N.sub.2, CH.sub.2N.sub.3, CH.sub.2N.sub.4, CH.sub.2N.sub.5), 2.81 (m, 1134H, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3, N.sub.3CH.sub.3, N.sub.4CH.sub.3, N.sub.5CH.sub.3), 1.45 (s, 1728H, Boc).

    [0559] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3): ? (ppm) 68.16 (s, P.sub.4), 67.94 (m, P.sub.1 P.sub.2, P.sub.3), 7.85 (s, P.sub.0).

    General Synthesis Procedure for Dendrimers 1-G.SUB.n.-HTFA from 1-G.SUB.n.-Boc

    [0560] Compound 1-G.sub.nBoc (200 mg) is dissolved in a CH.sub.2Cl.sub.2/trifluoroacetic acid 70/30 mixture (30 mL). After 30 min of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is subsequently co-evaporated 5 times with 3 mL of CH.sub.2Cl.sub.2 to give dendrimer 1-G.sub.n-HTFA in the form of a white powder. The yields are greater than 90%.

    Characterization of 1-G.SUB.1.-HTFA

    [0561] ##STR00168##

    [0562] .sup.1H NMR (400 MHz, CD.sub.3CN) ? (ppm): 2.64 (s), 2.77 (d, J=10.8 Hz), 4.11 (s), 4.47 (d, J=13.4 Hz), 6.93 (d, J=8.4 Hz), 7.23 (d, J=9.7 Hz), 7.47 (d, J=8.6 Hz).

    [0563] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 9.09 (s, P0), 67.80 (s, P1). The structure of dendrimer 1-G.sub.1-HTFA is represented in [FIG. 2].

    Characterization of 1-G.SUB.2.-HTFA

    [0564] ##STR00169##

    [0565] .sup.1H NMR (600 MHz, CD.sub.2Cl.sub.2): ? (ppm) 7.40-6.91 (m, 168H, CH-arom), 4.63-4.47 (d, .sup.3J.sub.HP=12.6 Hz, 36H, CH.sub.2N.sub.0H, CH.sub.2N.sub.1H), 4.40 (s, 48H, CH.sub.2N.sub.2H), 3.14-2.84 (m, 54H, N.sub.0CH.sub.3, N.sub.1CH.sub.3), 2.81 (s, 72H, N.sub.2CH.sub.3), 1.47 (brs, 216H, Boc).

    [0566] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.3CN) ? (ppm): 9.12 (s, P0), 67.74 (s, P2), 68.38 (s, P1).

    [0567] The structure of dendrimer 1-G.sub.2-HTFA is represented in [FIG. 3].

    Characterization of 1-G.SUB.3.-HTFA

    [0568] ##STR00170##

    [0569] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 9.10 (s, P0), 67.71 (s, (P3), 68.33 (s, P1, P2).

    [0570] The structure of dendrimer 1-G.sub.3-HTFA is represented in [FIG. 4].

    Characterization of 1-G.SUB.4.-HTFA

    [0571] ##STR00171##

    [0572] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 8.97 (s, P0), 67.72 (s, P4), 68.30 (s, P1, P2, P3).

    [0573] .sup.1H NMR (400 MHz, CD.sub.3CN) ? (ppm): 2.58-2.74 (m, 558H, N.sub.0CH.sub.3, N.sub.1CH.sub.3, N.sub.2CH.sub.3, N.sub.3CH.sub.3, N.sub.4CH.sub.3), 4.06-4.58 (m, 372, CH.sub.2N.sub.0, CH.sub.2N CH.sub.2N.sub.2, CH.sub.2N.sub.3, CH.sub.2N.sub.4), 6.65-7.87 (m, 744H, CH-arom).

    [0574] The structure of dendrimer 1-G.sub.4-HTFA is represented in [FIG. 5].

    Divergent Synthesis of 1st Generation Dendrimers Having Bis-Phosphonate Terminations

    [0575] Scheme 3 describes the reaction scheme for divergent synthesis of 1st generation dendrimers having bis-phosphonate terminations:

    ##STR00172## ##STR00173##

    Compound 3-G.SUB.1 .(OMe) from 1-G.SUB.1

    [0576] ##STR00174##

    [0577] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (12 mmol) is added to a solution of compound 1-G.sub.1 prepared previously (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (24 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is diluted in minimal THF then washed in a large volume of diethyl ether. After drying under reduced pressure, dendrimer 3-G.sub.1(OMe) is obtained in the form of a transparent oil at a yield of greater than 95%.

    [0578] .sup.31P-{.sup.1H} NMR (243 MHz, CDCl.sub.3) ? (ppm): 8.40 (s, N?P), 26.85 (s, P0), 68.32 (s, ?S);

    [0579] .sup.1H NMR (600 MHz, CDCl.sub.3) ? (ppm): 2.75 (d, .sup.3J.sub.HH=10.1 Hz, 24H, C.sub.1.sup.4CH.sub.2), 2.77 (d, .sup.3J.sub.HP=7.6 Hz, 18H, CH.sub.3), 3.06 (d, .sup.3J.sub.HH=7.7 Hz, 24H, C.sub.1.sup.4CH.sub.2CH.sub.2), 3.19 (d, .sup.2J.sub.HP=9.4 Hz, 48H, CH.sub.2P), 3.73 (d, .sup.3J.sub.HP=10.6 Hz, 144H, POMe), 6.94 (d, .sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2H), 7.07 (d, .sup.3J.sub.HH=8.1 Hz, 24H, C.sub.1.sup.2H), 7.18 (br d, .sup.3J.sub.HH=8.2 Hz, 36H, C.sub.0.sup.3 and C.sub.1.sup.3H);

    [0580] .sup.13C-{.sup.1H} NMR (151 MHz, CDCl.sub.3) ? (ppm): 33.05 (s, CH.sub.2), 33.64 s, (CH.sub.3N), 49.46 (dd, .sup.1J.sub.CP=157.3, .sup.3J.sub.CP=7.2 Hz, CH.sub.2P), 53.56-51.75 (m, POCH.sub.3), 53.47 (d, .sup.2J.sub.CP=10.3 Hz, C.sub.1.sup.4CH.sub.2), 58.22 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 120.91 (br d, .sup.3J.sub.CP=4.4 Hz, C.sub.0.sup.2 and C.sub.1.sup.2), 129.30 (s, C.sub.0.sup.3), 129.87 (s, C.sub.1.sup.3), 134.10 (br d, .sup.2J.sub.CP=4.5 Hz, C.sub.0.sup.4), 136.22 (s, C.sub.1.sup.4), 149.35 (d, .sup.2J.sub.CP=7.5 Hz, C.sub.1.sup.1), 150.01 (br s, C.sub.0.sup.1).

    [0581] The structure of dendrimer 3-G.sub.1(OMe) is represented in [FIG. 6].

    Compound 3-G.SUB.1 .(OH) from 3-G.SUB.1 .(OMe)

    [0582] ##STR00175##

    [0583] BrTMS (1.34, 10.2 mmol) is added dropwise to a solution of dendrimer 3-G.sub.1(OMe) (1 g, 0.17 mmol) in anhydrous CH.sub.3CN (30 mL) at 0? C. After stirring overnight, the mixture is evaporated to dryness under reduced pressure. The residue is stirred for one hour in MeOH (10 mL), then washed 2 times with MeOH (20 mL) then once with Et.sub.2O (20 mL). The solid obtained is dried under reduced pressure to give dendrimer 3-G.sub.1(OH) in the form of a white powder at a quantitative yield.

    [0584] .sup.31P NMR (162 MHz, D.sub.2O) ? (ppm): 7.36 (brs, POH), 8.35 (brs, POH), 68.53 (brs, PS).

    [0585] The structure of dendrimer 3-G.sub.1(OH) is represented in [FIG. 7].

    [0586] The compound 3-G.sub.1(OH) is subsequently converted into 3-G.sub.1(Ona)

    Compound 3-G.SUB.1.(ONa) from 3-G.SUB.1.(OH)

    [0587] ##STR00176##

    [0588] 24 equivalents of a 0.1 M aqueous solution of NaOH are added to a suspension of 3-G.sub.1(OH) in water, with stirring. The resulting solution is filtered over a microfilter at 0.4 ?M then lyophilized to give compound 3-G.sub.1(ONa) in the form of a white powder at a yield of 90%.

    [0589] .sup.31P-{.sup.1H} NMR (162 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 6.93 (s, PO), 9.59 (s, N?P), 68.77 (s, ?S);

    [0590] .sup.1H NMR (600 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 2.76 (d, .sup.3J.sub.HP=10.7 Hz, 18H, CH.sub.3), 3.13 (t, .sup.3J.sub.HH=8.8 Hz, 24H, C.sub.1.sup.4CH.sub.2), 3.47 (d, .sup.2J.sub.HP=11.9 Hz, 48H, CH.sub.2P), 3.72 (t, .sup.3J.sub.HH=8.6 Hz, 24H, C.sub.1.sup.4CH.sub.2CH.sub.2), 4.47 (d, .sup.2J.sub.HP=13.5 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.91 (d, .sup.2J.sub.HH=8.1 Hz, 12H, C.sub.0.sup.2H), 7.15 (d, .sup.2J.sub.HH=8.1 Hz, 24H, C.sub.1.sup.2H), 7.29 (d, .sup.2J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.3H), 7.38 (d, .sup.2J.sub.HH=8.2 Hz, 24H, C.sub.1.sup.3H);

    [0591] .sup.13C-{.sup.1H} NMR (151 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 29.07 (s, C.sub.1.sup.4CH.sub.2), 33.58 (s, CH.sub.3), 52.91 (d, .sup.1J.sub.CP=127.6 Hz, CH.sub.2P), 52.94 (s, C.sub.0.sup.4CH.sub.2), 57.81 (s, C.sub.1.sup.4CH.sub.2CH.sub.2), 121.14 (br s, C.sub.0.sup.2), 121.42 (d, .sup.3J.sub.CP=4.4 Hz C.sub.1.sup.2), 129.61 (s, C.sub.0.sup.3), 130.59 (s, C.sub.1.sup.3), 133.95 (s, C.sub.1.sup.4), 134.89 (s, C.sub.0.sup.4), 149.18 (s, C.sub.0.sup.1), 149.60 (d, .sup.3J.sub.CP=7.6 Hz, C.sub.1.sup.1) ppm.

    [0592] The structure of dendrimer 3-G.sub.1(ONa) is represented in [FIG. 8].

    Synthesis of compound 4-G.SUB.0 .from 1-G.SUB.0

    [0593] ##STR00177##

    [0594] 1-Aminohexane (5.5 mL, 41.8 mmol) is added to a solution of compound 1-G.sub.0 (2 g, 2.32 mmol) in THF (40 mL). After stirring overnight at ambient temperature, the mixture is concentrated to dryness then washed 3-4 times with MeOH to give the dendrimer 4-G.sub.0 in the form of a white powder at a quantitative yield.

    [0595] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.2Cl.sub.2) ? (ppm): 8.46 (s, P?N).

    [0596] .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) ? (ppm): 0.79-1.10 (m, 18H, CH.sub.3), 1.29-1.47 (m, 36H, CH.sub.2), 1.68-1.77 (m, 12H, CH.sub.2), 3.63 (td, .sup.3J.sub.HH=7.1, .sup.4J.sub.HH=1.3 Hz, 12H, CH.sub.2N), 7.00 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 7.58 (d, .sup.3J.sub.HH=8.7 Hz, 12H, C.sub.0.sup.3H), 8.23 (s, 6H, CH?N).

    Compound 4-G.SUB.0 .from 4-G.SUB.0

    [0597] ##STR00178##

    [0598] NaBH.sub.4(672 mg, 17.75 mmol) is added to a solution of dendrimer 4-G0 (2 g, 1.4 mmol) in a THF/MeOH (30/10) mL mixture. After stirring overnight at ambient temperature, the mixture is concentrated to dryness. The crude residue is diluted in 200 mL of DCM then washed once with 50 mL distilled water. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product is subsequently dissolved in MeOH (30 mL) to which 20 mL of HCl (1 M in MeOH) is added. After 2 h without stirring, the solution is filtered then concentrated under reduced pressure. The residue is subsequently washed 3 times with 25 mL of DCM to give a white powder. The product is dissolved in a DCM/THF mixture (75/25 mL), to which is added 25 mL of a solution of NaOH (2 M) then extracted 4-5 times with 200 mL of DCM. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give dendrimer 4-G.sub.0 in the form of a colorless oil at a yield of 78%.

    [0599] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 8.72 (s, P?N).

    [0600] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 0.73-1.09 (m, 18H, CH.sub.3)), 1.13-1.42 (m, 48H, CH.sub.2), 1.45-1.55 (m, 12H, CH.sub.2), 2.60 (t, .sup.3J.sub.HH=7.2 Hz, 12H, CH.sub.2N), 3.73 (s, 12H, C.sub.0.sup.4CH.sub.2), 6.90 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 7.13 (d, .sup.3J.sub.HH=8.6 Hz, 12H, C.sub.0.sup.3H).

    Compound 4-G.SUB.1 .from 4-G.SUB.0

    [0601] ##STR00179##

    [0602] A solution of dendrimer 4-G.sub.0 (1 g, 0.72 mmol) is added dropwise to a solution of PSCl.sub.3 (4 mL, 39.36 mmol) in DCM (100 mL) at ?70? C. in the presence of Et.sub.3N (0.91 mL, 6.57 mmol) in DCM (40 mL) over a duration of 30 min. After stirring overnight, the reaction mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of DCM then filtered over silica gel to give dendrimer 4-G.sub.1 in the form of a transparent oil at a yield of 35%.

    [0603] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.36 (s, P?N), 63.09 (s, PS).

    [0604] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.89 (t, .sup.3J.sub.HH=6.9 Hz, 18H, CH.sub.3), 1.23-1.47 (m, 36H, CH.sub.2), 1.57-1.64 (m, 12H, CH.sub.2), 3.23 (dt, .sup.3J.sub.HP=18.0, .sup.3J.sub.HH=7.8 Hz, 12H, CH.sub.2N), 4.63 (d, .sup.3J.sub.HP=16.9 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.99 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 7.23 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H).

    [0605] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 14.01 (s, CH.sub.3), 22.53 (s, CH.sub.2), 26.33 (s, CH.sub.2), 26.90 (d, .sup.2J.sub.CP=2.9 Hz, CH.sub.2N), 31.36 (s, CH.sub.2), 47.38 (s, CH.sub.2), 50.11 (d, .sup.2J.sub.CP=4.8 Hz, C.sub.0.sup.4CH.sub.2), 121.22 (br s, C.sub.0.sup.2), 129.16 (s, C.sub.0.sup.3), 132.67 (d, .sup.3J.sub.CP=5.0 Hz, C.sub.0.sup.4), 150.22 (dd, .sup.2J.sub.CP=5.1, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1)

    Compound 4-G.SUB.1 .(OMe) from 4-G.SUB.1

    [0606] ##STR00180##

    [0607] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (12 mmol) is added to a solution of compound 4-G.sub.1 (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (24 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is diluted in minimal THF then washed in a large volume of diethyl ether. After drying under reduced pressure, dendrimer 4-G.sub.1(OMe) is obtained in the form of a transparent oil at a quantitative yield.

    [0608] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.23 (s, P?N), 26.89 (s, POMe), 68.00 (s, PS).

    [0609] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.78 (t, .sup.3J.sub.HH=6.6 Hz, 18H, CH.sub.3), 1.10-1.26 (m, 36H, CH.sub.2), 1.41-1.47 (m, 12H, CH.sub.2), 2.75 (t, .sup.3J.sub.HH=7.6 Hz, 24H, CH.sub.2-C.sub.1.sup.4), 3.04 (t, .sup.3J.sub.HH=7.7 Hz, 24H, CH.sub.2N), 3.09-3.15 (m, 12H, CH.sub.2NP), 3.19 (d, .sup.2J.sub.HP=9.3 Hz, 18H, CH.sub.2P), 3.65-3.79 (m, 144H, POMe), 4.53 (d, .sup.3J.sub.HP=13.1 Hz, 12H, CH.sub.2-C.sub.0.sup.4), 6.95 (d, .sup.3J.sub.HH=8.1 Hz, 12H, C.sub.0.sup.2H), 7.06 (d, .sup.3J.sub.HH=8.2 Hz, 24H, C.sub.1.sup.2H), 7.16 (d, .sup.3J.sub.HH=8.2 Hz, 24H, C.sub.1.sup.2H), 7.22 (d, .sup.3J.sub.HH=8.3 Hz, 24H, C.sub.0.sup.3H).

    [0610] The structure of dendrimer 4-G.sub.1(OMe) is represented in [FIG. 9].

    Compound 4-G.SUB.1 .(OH) from 4-G.SUB.1.(OMe)

    [0611] ##STR00181##

    [0612] BrT?S (1.25, 9.48 mmol) is added to a solution of dendrimer 4-G.sub.1 (OMe) (1 g, 0.16 mmol) in anhydrous CH.sub.3CN (30 mL) at 0? C. After stirring overnight, the mixture is evaporated to dryness under reduced pressure. The residue is stirred for one hour in ?eOH (10 mL), then washed 2 times with ?eOH (20 mL) then once with Et.sub.2O (20 mL). The solid obtained is dried under reduced pressure to give dendrimer 4-G.sub.1(OH) in the form of a white powder at a quantitative yield.

    [0613] .sup.31 ?-{.sup.1H} N?R (162 ?Hz, D.sub.2O) ? (ppm): 8.20 (brs, ?OH)

    [0614] The structure of dendrimer 4-G.sub.1(OH) is represented in [FIG. 10].

    [0615] The compound 4-G.sub.1(OH) is subsequently converted into 4-G.sub.1(ONa)

    Compound 4-G.SUB.1 .(ONa) from 4-G.SUB.1 .(OH)

    [0616] ##STR00182##

    [0617] 24 equivalents of a 0.1? aqueous solution of NaOH are added to a suspension of 4-G.sub.1(OH) in water, with stirring. The resulting solution is filtered over a microfilter at 0.4 ?M then lyophilized to give compound 4-G.sub.1(ONa) in the form of a white powder at a yield of 88%.

    [0618] .sup.31?-{.sup.1H} N?R (162 ?Hz, D.sub.2O) ? (ppm) 6.64 (s, ?OHONa), 9.50 (s, ?=N), 68.66 (s, ?S).

    [0619] The structure of dendrimer 4-G.sub.1(ONa) is represented in [FIG. 11].

    Compound 5-G.SUB.0 .from 1-G.SUB.0

    [0620] ##STR00183##

    [0621] 1-Aminooctane (6.8 mL, 41.8 mmol) is added to a solution of compound 1-G.sub.0 (2 g, 2.32 mmol) in THF (40 mL). After stirring overnight at ambient temperature, the mixture is concentrated to dryness then washed 3-4 times with ?eOH to give the dendrimer 5-G.sub.0 in the form of a white powder at a quantitative yield.

    [0622] .sup.31?-{.sup.1H} N?R (121 ?Hz, CD.sub.2Cl.sub.2) ? (ppm): 8.46 (s, ?=N).

    [0623] .sup.1H N?R (300 ?Hz, CD.sub.2Cl.sub.2) ? (ppm): 0.73-1.13 (m, 18H, CH.sub.3), 1.19-1.45 (m, 60H, CH.sub.2), 1.78-1.66 (m, 12H, CH.sub.2), 3.62 (td, .sup.3J.sub.HH 7.1, .sup.4J.sub.HH 1.3 Hz, 12H, CH.sub.2N), 6.99 (d, .sup.3J.sub.HH 8.6 Hz, 12H, C.sub.0.sup.2H), 7.58 (d, .sup.3J.sub.HH 8.7 Hz, 12H, C.sub.0.sup.3H), 8.22 (s, 6H, CH?N).

    [0624] .sup.13C-{.sup.1H} NMR (75 MHz, CD.sub.2Cl.sub.2) ? (ppm): 13.86 (s, CH.sub.3), 22.66 (s, CH.sub.2), 27.43 (s, CH.sub.2), 29.31 (s, CH.sub.2), 29.47 (s, CH.sub.2), 31.04 (s, CH.sub.2), 31.88 (s, CH.sub.2), 61.67 (s, CH.sub.2N), 120.93 (d, .sup.3J.sub.CP=2.9 Hz, C.sub.0.sup.2H), 129.19 (s, C.sub.0.sup.3H), 133.78 (s, C.sub.0.sup.4), 151.80 (d, .sup.2J.sub.CP=7.6 Hz, C.sub.0.sup.1), 158.93 (s, C?N).

    Compound 5-G.SUB.0 .from 5-G.SUB.0

    [0625] ##STR00184##

    [0626] NaBH.sub.4 (594 mg, 15.68 mmol) is added to a solution of dendrimer 5-G.sub.0 (2 g, 1.3 mmol) in a THF/MeOH (30/10) mL mixture. After stirring overnight at ambient temperature, the mixture is concentrated to dryness. The crude residue is diluted in 200 mL of DCM then washed once with 50 mL distilled water. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The product is subsequently dissolved in MeOH (30 mL) to which 20 mL of HCl (1 M in MeOH) is added. After 2 h without stirring, the solution is filtered then concentrated under reduced pressure. The residue is subsequently washed 3 times with 25 mL of DCM to give a white powder. The product is dissolved in a DCM/THF mixture (75/25 mL), to which is added 25 mL of a solution of NaOH (2 M) then extracted 4-5 times with 200 mL of DCM. The organic phase is recovered, dried with Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give dendrimer 5-G.sub.0 in the form of a colorless oil at a yield of 65%.

    [0627] .sup.31P-{.sup.1H} NMR (121 MHz, CD.sub.2Cl.sub.2) ? (ppm): 8.92 (s, P?N).

    [0628] .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) ? (ppm): 0.70-1.13 (m, 18H, CH.sub.3), 1.23-1.45 (m, 60H, CH.sub.2), 1.46-1.66 (m, 12H, CH.sub.2), 2.64 (t, .sup.3J.sub.HH=7.1 Hz, 12H, CH.sub.2N), 3.77 (s, 12H, C.sub.0.sup.4CH.sub.2), 6.91 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.2H), 7.22 (d, .sup.3J.sub.HH=8.5 Hz, 12H, C.sub.0.sup.3H).

    [0629] .sup.13C-{.sup.1H} NMR (75 MHz, CD.sub.2Cl.sub.2) ? (ppm): 13.88 (s, CH.sub.3), 22.68 (s, CH.sub.2), 27.41 (s, CH.sub.2), 29.33 (s, CH.sub.2), 29.60 (s, CH.sub.2), 30.11 (s, CH.sub.2), 31.88 (s, CH.sub.2), 49.55 (s, CH.sub.2), 53.31 (s, CH.sub.2), 115.12-124.47 (m, C.sub.0.sup.2), 129.03 (s, C.sub.0.sup.3), 137.59 (s, C.sub.0.sup.4), 149.37 (dd, .sup.2J.sub.CP=5.1, .sup.4J.sub.CP=2.5 Hz, C.sub.0.sup.1).

    Compound 5-G.SUB.1 .from 5-G.SUB.0

    [0630] ##STR00185##

    [0631] A solution of dendrimer 5-G.sub.0 (1 g, 0.64 mmol) is added dropwise to a solution of PSCl.sub.3 (4 mL, 39.36 mmol) in DCM (100 mL) brought to ?70? C. in the presence of Et.sub.3N (0.81 mL, 5.84 mmol) in DCM (40 mL) over a duration of 30 min. After stirring overnight, the reaction mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of DCM then filtered over silica gel to give dendrimer 5-G.sub.1 in the form of a transparent oil at a yield of 25%.

    [0632] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.2Cl.sub.2) ? (ppm): 8.42 (s, P?N), 63.04 (s, PS).

    [0633] .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) ? (ppm): 0.91 (t, .sup.3J.sub.HH=6.7 Hz, 18H, CH.sub.3), 1.14-1.40 (m, 72H, CH.sub.2), 1.59-1.68 (m, 24H, CH.sub.2), 3.00-3.50 (m, 12H, CH.sub.2N), 4.67 (d, .sup.3J.sub.HP=17.0 Hz, 12H, C.sub.0.sup.4CH.sub.2), 7.02 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2H), 7.29 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3H).

    Compound 5-G.SUB.1 .(OMe) from 5-G.SUB.1

    [0634] ##STR00186##

    [0635] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (12 mmol) is added to a solution of compound 5-G.sub.1 (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (24 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is diluted in minimal THF then washed in a large volume of diethyl ether. After drying under reduced pressure, dendrimer 5-G.sub.1(OMe) is obtained in the form of a transparent oil at a quantitative yield.

    [0636] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.22 (s, P?N), 26.89 (s, POMe), 68.01 (s, PS).

    [0637] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.83 (t, .sup.3J.sub.HH=7.0 Hz, 18H, CH.sub.3), 1.01-1.41 (m, 60H, CH.sub.2), 1.45 (br s, 12H, CH.sub.2), 2.77 (t, .sup.3J.sub.HH=7.5 Hz, 24H, C.sub.1.sup.4CH.sub.2), 3.06 (t, .sup.3J.sub.HH=7.7 Hz, 24H, CH.sub.2N), 3.09-3.15 (m, 12H, CH.sub.2NPS), 3.20 (d, .sup.2J.sub.HP=9.3 Hz, 48H, CH.sub.2P), 3.74 (d, .sup.3J.sub.HP=10.6, 1.5 Hz, 72H, POMe), 3.75 (d, .sup.3J.sub.HP=10.6, 1.5 Hz, 72H, POMe), 4.55 (d, .sup.3J.sub.HP=13.1 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.96 (d, .sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2H), 7.02-7.12 (m, 24H, C.sub.1.sup.2H), 7.18 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.24 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3H).

    [0638] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 14.11 (s, CH.sub.3), 22.61 (s, CH.sub.2), 26.81 (s, CH.sub.2), 27.62 (s, CH.sub.2), 29.18 (s, CH.sub.2), 31.72 (s, CH.sub.2), 33.07 (s C.sub.1.sup.4CH.sub.2), 45.74 (br s, CH.sub.2NS), 49.45 (dd, .sup.1J.sub.CP=157.2, .sup.3J.sub.CP=7.1 Hz, CH.sub.2P), 49.46 (br s, C.sub.0.sup.4CH.sub.2), 52.59-52.71 (m, POMe), 58.30 (t, .sup.3J.sub.CP=7.7 Hz, CH.sub.2N), 120.90 (s, C.sub.0.sup.2H), 121.02 (d, .sup.2J.sub.CP=4.7 Hz, C.sub.0.sup.2H), 129.39 (s, C.sub.0.sup.3H), 129.77 (s, C.sub.1.sup.3H), 134.28 (s, C.sub.0.sup.4), 136.09 (s, C.sub.1.sup.4), 149.54 (d, .sup.2J.sub.CP=7.8 Hz, C.sub.1.sup.1), 150.00 (d, .sup.2J.sub.CP=4.5 Hz, C.sub.0.sup.1).

    [0639] The structure of dendrimer 5-G.sub.1(OMe) is represented in [FIG. 12].

    Compound 5-G.SUB.1.(OH) from 5-G.SUB.1.(OMe)

    [0640] ##STR00187##

    [0641] BrTMS (1.22, 9 mmol) is added to a solution of dendrimer 5-G.sub.1(OMe) (1 g, 0.15 mmol) in anhydrous CH.sub.3CN (30 mL) at 0? C. After stirring overnight, the mixture is evaporated to dryness under reduced pressure. The residue is stirred for one hour in MeOH (10 mL), then washed 2 times with MeOH (20 mL) then once with Et.sub.2O (20 mL). The solid obtained is dried under reduced pressure to give dendrimer 5-G.sub.1(OH) in the form of a white powder at a quantitative yield.

    [0642] .sup.31P-{.sup.1H} NMR (162 MHz, D.sub.2O) ? (ppm): 7.19 (brs, POH).

    [0643] The structure of dendrimer 5-G.sub.1(OH) is represented in [FIG. 13].

    [0644] The compound 5-G.sub.1(OH) is subsequently converted into 5-G.sub.1(ONa)

    Compound 5-G.SUB.1 .(ONa) from 5-G.SUB.1 .(OH)

    [0645] ##STR00188##

    [0646] 24 equivalents of a 0.1 M aqueous solution of NaOH are added to a suspension of 5-G.sub.1(OH) in water, with stirring. The resulting solution is filtered over a microfilter at 0.4 ?M then lyophilized to give compound 5-G.sub.1(ONa) in the form of a white powder at a yield of 85%.

    [0647] .sup.31P-{.sup.1H} NMR (243 MHz, D.sub.2O) ? (ppm): 6.64 (s, N?P), 9.50 (s, PO), 68.66 (s, PS).

    [0648] The structure of dendrimer 5-G.sub.1(ONa) is represented in [FIG. 14].

    Semi-Convergent Synthesis of 1st Generation Dendrimers Having Bisphosphonate Terminations

    [0649] Scheme 4 describes the reaction scheme for divergent synthesis of 1st generation dendrimers having bis-phosphonate terminations:

    ##STR00189## ##STR00190##

    [0650] Compound 3a

    ##STR00191##

    [0651] To a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (Fu H. et al. Molecules, 2014, 16, 17715-17726) (1 g, 4.83 mmol) in THF (30 mL) a solution of methylamine (8M in EtOH) (1.8, 14.49 mmol) is added. After stirring overnight at ambient temperature, the mixture is concentrated to dryness to give the product 3a in the form of a colorless oil at a yield of 95%.

    [0652] .sup.1H NMR (300 MHz, CD.sub.3OD) ? (ppm): 1.39-1.74 (m, 3H, CH.sub.2), 1.75-1.92 (m, 2H, CH.sub.2), 1.90-2.06 (m, 1H, CH.sub.2O), 3.55-3.62 (m, 1H, CH.sub.2O), 3.79-3.87 (m, 1H, CH.sub.2), 5.46 (t, .sup.3J.sub.HH=3.1 Hz, 1H, OCHO), 7.08 (d, .sup.3J.sub.HH=8.8 Hz, 2H, C.sub.0.sup.2H), 7.63 (d, .sup.3J.sub.HH=8.8 Hz, 2H, C.sub.0.sup.3H), 8.21 (q, .sup.4J.sub.HH=1.6 Hz, 1H, CH?N).

    [0653] .sup.13C-{.sup.1H} NMR (75 MHz, CD.sub.3OD) ? (ppm): 18.46 (s, CH.sub.2), 24.89 (s, CH.sub.2), 29.95 (s, CH.sub.2), 46.32 (s, CH.sub.3), 61.73 (s, CH.sub.2O), 96.10 (s, CHO), 116.17 (s, C.sub.0.sup.2), 129.22 (s, C.sub.0.sup.4), 129.30 (s, C.sub.0.sup.3), 159.41 (s, C.sub.0.sup.4), 163.46 (s, C?N).

    [0654] Compounds 3b

    ##STR00192##

    [0655] Pd/C at 10% (225 mg) and MeOH (40 mL) are introduced to a solution of compound 3a (1 g, 4.5 mmol) in a Fisher-Porter type tube. The tube is slowly placed under vacuum so as to evacuate the air. The H2 pressure is subsequently adjusted to 5 bar. The reaction mixture is stirred for 2 hours at ambient temperature. After slow depressurization, the reaction mixture is recovered, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (eluent: EtOAc) to obtain compound 3b in the form of a transparent oil at a yield of 80%.

    [0656] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 1.33-1.72 (m, 3H, CH.sub.2), 1.77-1.82 (m, 2H, CH.sub.2), 1.87-2.07 (m, 1H, CH.sub.2O), 2.36 (s, 3H, CH.sub.3), 3.50-3.57 (m, 1H, CH.sub.2O), 3.61 (s, 2H, CH.sub.2N), 3.76-3.99 (m, 1H, CH.sub.2), 5.34 (t, .sup.3J.sub.HH=3.3 Hz, 1H, OCHO), 6.96 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.09-7.26 (m, 2H, C.sub.0.sup.2H).

    [0657] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3) ? (ppm): 18.78 (s, CH.sub.2), 25.16 (s, CH.sub.2), 30.33 (s, CH.sub.2), 35.63 (s, CH.sub.3), 55.31 (s, CH.sub.2N), 61.96 (s, CH.sub.2O), 96.38 (s, OCHO), 116.36 (s, C.sub.0.sup.2), 129.25 (s, C.sub.0.sup.3), 132.78 (s, C.sub.0.sup.3), 156.12 (s, C.sub.0.sup.4).

    [0658] Compound 4b

    ##STR00193##

    [0659] 1-Aminohexane (1.9 mL, 14.49 mmol) is added to a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (1 g, 4.83 mmol) in THF (30 mL). After stirring overnight at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue obtained, Pd/C at 10% (241 mg) and MeOH (40 mL) are introduced into a Fisher-Porter-type tube. The tube is slowly placed under vacuum so as to evacuate the oxygen. The H2 pressure is subsequently adjusted to 5 bar. The reaction mixture is stirred for 2 hours at ambient temperature. After slow depressurization, the reaction mixture is recovered, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (eluent: EtOAc) to obtain compound 4b in the form of a transparent oil at a yield of 70%.

    [0660] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 0.76-1.05 (m, 3H, CH.sub.3), 1.17-1.43 (m, 3H, CH.sub.2), 1.43-1.59 (m, 3H, CH.sub.2), 1.59-1.76 (m, 3H, CH.sub.2), 1.75-1.95 (m, 3H, CH.sub.2), 1.90-2.04 (m, 3H, CH.sub.2), 2.61 (t, .sup.3J.sub.HH=7.1 Hz, 2H, CH.sub.2N), 3.56-3.63 (m, 1H, CH.sub.2O), 3.72 (s, 2H, C.sub.0.sup.4CH.sub.2), 3.88-3.96 (m, 1H, CH.sub.2O), 5.40 (t, .sup.3J.sub.HH=3.3 Hz, 1H, OCH.sub.2O), 7.01 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.23 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.3H).

    [0661] .sup.13C-{.sup.1H} NMR (75 MHz, CDCl.sub.3) ? (ppm): 14.04 (s, CH.sub.3), 18.82 (s, CH.sub.2), 22.62 (s, CH.sub.2), 25.24 (s, CH.sub.2), 27.06 (s, CH.sub.2), 30.09 (s, CH.sub.2), 30.39 (s, CH.sub.2), 31.80 (s, CH.sub.2), 49.46 (s, CH.sub.2), 53.54 (s, CH.sub.2N), 61.97 (s, CH.sub.2O), 96.41 (s, OCHO), 116.36 (s, C.sub.0.sup.2), 129.12 (s, C.sub.0.sup.3), 133.72 (s, C.sub.0.sup.4), 156.01 (s, C.sub.0.sup.1).

    [0662] Compound 5b

    ##STR00194##

    [0663] 1-Aminooctane (2.4 mL, 14.49 mmol) is added to a solution of 4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (1 g, 4.83 mmol) in THF (30 mL). After stirring overnight at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue obtained, Pd/C at 10% (241 mg) and MeOH (40 mL) are introduced into a Fisher-Porter-type tube. The tube is slowly placed under vacuum so as to evacuate the oxygen. The H2 pressure is subsequently adjusted to 5 bar. The reaction mixture is stirred for 2 hours at ambient temperature. After slow depressurization, the reaction mixture is recovered, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (eluent: EtOAc) to obtain compound 5b in the form of a transparent oil at a yield of 76%.

    [0664] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.90 (t, .sup.3J.sub.HH=6.8 Hz, 3H, CH.sub.3), 1.28-1.34 (m, 10H, CH.sub.2), 1.45-1.53 (m, 3H, CH.sub.2), 1.54-1.79 (m, 2H, CH.sub.2), 1.85-1.90 (m, 2H, CH.sub.2), 1.97-2.15 (m, 1H, CH.sub.2), 2.62 (t, .sup.3J.sub.HH=7.1 Hz, 2H, CH.sub.2N), 3.59-3.64 (m, 1H, CH.sub.2O), 3.74 (s, CH.sub.2C.sub.0.sup.4), 3.91-3.97 (m, 1H, CH.sub.2O), 5.42 (t, .sup.3J.sub.HH=3.4 Hz, 1H, CHO), 7.02 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.24 (d, .sup.3J.sub.HH=8.5 Hz, 1H, C.sub.0.sup.3H).

    [0665] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 14.11 (s, CH.sub.3), 18.85 (s, CH.sub.2), 22.67 (s, CH.sub.2), 25.24 (s, CH.sub.2), 27.40 (s, CH.sub.2), 29.28 (s, CH.sub.2), 29.55 (s, CH.sub.2), 30.12 (s, CH.sub.2), 30.41 (s, CH.sub.2), 31.84 (s, CH.sub.2), 49.47 (s, CH.sub.2), 53.56 (s, CH.sub.2N), 62.04 (s, CH.sub.2O), 96.45 (s, OCHO), 116.39 (s, C.sub.0.sup.2), 129.18 (s, C.sub.0.sup.2), 133.70 (s, C.sub.0.sup.4), 156.02 (s, C.sub.0.sup.1).

    [0666] Compound 3c

    ##STR00195##

    [0667] A solution of dendrimer 3b (1 g, 4.52 mmol) is added dropwise to a solution of PSCl.sub.3 (2.2 mL, 22.6 mmol) in DCM (100 mL) in the presence of Et.sub.3N (0.62 mL, 4.52 mmol) in DCM (40 mL) over a duration of 30 min. After 4 hours of stirring at ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of DCM then filtered over silica gel to give compound 3c in the form of a transparent oil at a yield of 85%.

    [0668] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 63.18 (s, PS).

    [0669] Compound 4c

    ##STR00196##

    [0670] A solution of dendrimer 4b (1 g, 3.43 mmol) is added dropwise to a solution of PSCl.sub.3 (1.73 mL, 17.18 mmol) in DCM (100 mL) brought to ?70? C. in the presence of Et.sub.3N (0.47 mL, 3.43 mmol) in DCM (40 mL) over a duration of 30 min. After stirring overnight, the reaction mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of DCM then filtered over silica gel to give compound 4c in the form of a transparent oil at a yield of 73%.

    [0671] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 63.01 (s, PS).

    [0672] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.79-0.98 (m, 3H, CH.sub.3), 1.15-1.33 (m, 6H, CH.sub.2), 1.54-1.75 (m, 5H, CH.sub.2), 1.82-1.93 (m, 2H, CH.sub.2), 1.95-2.06 (m, 1H, CH.sub.2), 3.20-3.36 (m, 2H, CH.sub.2N), 3.56-3.68 (m, 1H, CH.sub.2O), 3.88-3.94 (m, 1H, CH.sub.2O), 4.57 (d, .sup.3J.sub.HP=16.1 Hz, 2H, C.sub.0.sup.4CH.sub.2), 5.41 (t, .sup.3J.sub.HH=3.4 Hz, 1H, OCHO), 7.04 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.25 (d, .sup.3J.sub.HH=8.6 Hz, 1H, C.sub.0.sup.3H).

    [0673] Compound 5c

    ##STR00197##

    [0674] A solution of dendrimer 5b (1 g, 3.13 mmol) is added dropwise to a solution of PSCl.sub.3 (1.58 mL, 15.67 mmol) in DCM (100 mL) brought to ?70? C. in the presence of Et.sub.3N (0.43 mL, 3.13 mmol) in DCM (40 mL) over a duration of 30 min. After stirring overnight, the reaction mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently dissolved in 200 mL of DCM then filtered over silica gel to give compound 4c in the form of a transparent oil at a yield of 70%.

    [0675] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 62.92 (s, PS).

    [0676] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.90 (t, .sup.3J.sub.HH=6.9 Hz, 3H), 1.16-1.42 (m, 1 OH, CH.sub.2), 1.52-1.78 (m, 5H, CH.sub.2), 1.85-1.96 (m, 2H, CH.sub.2), 1.99-2.09 (m, 1H, CH.sub.2), 3.21-3.32 (m, 2H, CH.sub.2N), 3.57-3.71 (m, 1H, CH.sub.2-0), 3.90-3.96 (m, 1H, CH.sub.2O), 4.59 .sup.3J.sub.HP=16.1 Hz, 2H, C.sub.0.sup.4CH.sub.2), 5.43 (t, .sup.3J.sub.HH=3.3 Hz, 1H, OCH.sub.2O), 7.06 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.27 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.2H).

    [0677] Compound 3d

    ##STR00198##

    [0678] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (2 mmol) is added to a solution of compound 3c (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (4 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is subsequently purified by silica gel chromatographic column with an eluent mixture (MeOH/EtOAc) to give, after elimination of the solvents under reduced pressure, compound 3d in the form of a transparent oil at a yield of 85%.

    [0679] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 26.95 (s, POMe), 68.48 (s, P?N).

    [0680] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.58-1.72 (m, 3H, CH.sub.2), 1.81-1.94 (m, 2H, CH.sub.2), 1.96-2.05 (m, 1H, CH.sub.2), 2.78-2.83 (m, 7H, C.sub.1.sup.4CH.sub.2, CH.sub.3N), 3.09 (t, .sup.3J.sub.HH=7.6 Hz, 4H, CH.sub.2N), 3.22 (d, .sup.3J.sub.HH=8.9 Hz, 8H,), 3.55-3.67 (m, 1H, CH.sub.2O), 3.75 (d, .sup.3J.sub.HP=10.3 Hz, 24H, POMe), 3.89-3.95 (m, 1H, CH.sub.2-0), 4.44 (d, .sup.3J.sub.HP=12.0 Hz, 2H), 5.41 (t, .sup.3J.sub.HH=3.3 Hz, 1H, OCH.sub.2O), 6.99 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.12 (d, .sup.3J.sub.HH=8.4, 4H, C.sub.1.sup.2H), 7.16-7.25 (m, 6H, C.sub.0.sup.3H, C.sub.1.sup.3H).

    [0681] Compound 4d

    ##STR00199##

    [0682] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (2 mmol) is added to a solution of compound 4c (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (4 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is subsequently purified by silica gel chromatographic column with an eluent mixture (MeOH/EtOAc) to give, after elimination of the solvents under reduced pressure, compound 4d in the form of a transparent oil at a yield of 81%.

    [0683] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.60 (s, POMe), 67.70 (s, PS).

    [0684] Compound 5d

    ##STR00200##

    [0685] Phenol aminobismethylene phosphonate derived from tyramine (see WO 2005/052031 A1) (2 mmol) is added to a solution of compound 5c (1 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (4 mmol). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The crude residue is subsequently purified by silica gel chromatographic column with an eluent mixture (MeOH/EtOAc) to give, after elimination of the solvents under reduced pressure, compound 5d in the form of a transparent oil at a yield of 75%.

    [0686] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.92 (s, POMe), 68.02 (s, PS).

    [0687] Compound 3e

    ##STR00201##

    [0688] Pyridinium p-toluenesulfonate (1.5 mmol) is added to a solution of compound 3d (1 mmol) in MeOH (30 mL). The reaction mixture is stirred overnight at ambient temperature. The solvent is eliminated under reduced pressure and the residue is purified by silica gel chromatography (eluent: MeOH/AcOEt) to give, after elimination of the solvents under reduced pressure, compound 3e in the form of a transparent oil at a yield of 80%.

    [0689] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 26.76 (s, POMe), 68.38 (s, PS).

    [0690] Compound 4e

    ##STR00202##

    [0691] Pyridinium p-toluenesulfonate (1.5 mmol) is added to a solution of compound 4d (1 mmol) in MeOH (30 mL). The reaction mixture is stirred overnight at ambient temperature. The solvent is eliminated under reduced pressure and the residue is purified by silica gel chromatography (eluent: MeOH/EtOAc) to give, after elimination of the solvents under reduced pressure, compound 3e in the form of a transparent oil at a yield of 78%.

    [0692] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 26.70 (s, POMe), 68.2 (s, PS).

    [0693] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 0.74-0.91 (m, 3H, CH.sub.3), 1.11-1.39 (m, 6H, CH.sub.2), 1.58 (br s, 2H, CH.sub.2), 2.75 (t, .sup.3J.sub.HH=7.8 Hz, 4H, C.sub.1.sup.4CH.sub.2), 2.91-3.17 (m, 6H, CH.sub.2N, CH.sub.2N), 3.74 (d, .sup.3J.sub.HP=10.6, 12H, POMe), 3.75 (d, .sup.3J.sub.HP=10.6, 12H, POMe), 4.38 (d, .sup.3J.sub.HH=14.1 Hz, 2H, C.sub.0.sup.4CH.sub.2), 6.61 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.2H), 6.70 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.3H), 6.91-7.21 (m, 8H, C.sub.1.sup.2H, C.sub.1.sup.3H), 8.80 (s, 1H, OH).

    [0694] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 13.99 (s, CH.sub.3), 22.57 ((s, CH.sub.2), 26.57 (s, CH.sub.2), 27.00 (s, CH.sub.2), 31.50 (s, CH.sub.2), 33.20 (s, CH.sub.2), 44.66 (br s, CH.sub.2NP), 48.96 (d, .sup.2J.sub.CP=8.3 Hz, C.sub.0.sup.4CH.sub.2), 49.51 (dd, .sup.1J.sub.CP=157.7, .sup.2J.sub.CP=7.3 Hz, CH.sub.2P), 52.78 (m, POCH.sub.3), 58.38 (t, .sup.3J.sub.CP=7.4 Hz, CH.sub.2N), 114.87 (s, C.sub.0.sup.2), 121.33 (d, .sup.3J.sub.CP=4.8 Hz, C.sub.1.sup.2), 127.57 (d, .sup.3J.sub.CP=3.5 Hz, C.sub.0.sup.4), 129.64 (s, C.sub.1.sup.3), 129.76 (s, C.sub.0.sup.3), 135.73 (s, C.sub.1.sup.4), 149.33 (d, .sup.2J.sub.HP=7.2 Hz, C.sub.1.sup.1), 156.70 (s, C.sub.0.sup.1).

    [0695] Compound 5e

    ##STR00203##

    [0696] Pyridinium p-toluenesulfonate (1.5 mmol) is added to a solution of compound 5d (1 mmol) in MeOH (30 mL). The reaction mixture is stirred overnight at ambient temperature. The solvent is eliminated under reduced pressure and the residue is purified by silica gel chromatography (eluent: MeOH/EtOAc) to give, after elimination of the solvents under reduced pressure, compound 5e in the form of a transparent oil at a yield of 82%.

    [0697] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.72 (s, POMe), 68.41 (s, PS).

    Compounds 3-G.SUB.1.(OMe) from 3e

    [0698] ##STR00204##

    [0699] Hexachlorocyclotriphosphazene (60 mg, 0.17 mmol) is added to a solution of compound 3e (1 g, 1.04 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (794 mg, 2.08 mmol). After stirring overnight at 45? C., the mixture is centrifuged, filtered then concentrated under reduced pressure. Dendrimer 3-G.sub.1 was obtained in the form of a transparent oil at a yield of 90%.

    [0700] .sup.31P-{.sup.1H} NMR (243 MHz, CDCl.sub.3) ? (ppm): 8.40 (s, N?P), 26.85 (s, PO), 68.32 (s, PS);

    [0701] .sup.1H NMR (600 MHz, CDCl.sub.3) ? (ppm): 2.75 (d, .sup.3J.sub.HH=10.1 Hz, 24H, C.sub.1.sup.4CH.sub.2), 2.77 (d, .sup.3J.sub.HP=7.6 Hz, 18H, CH.sub.3), 3.06 (d, .sup.3J.sub.HH=7.7 Hz, 24H, C.sub.1.sup.4CH.sub.2CH.sub.2), 3.19 (d, .sup.2J.sub.HP=9.4 Hz, 48H, CH.sub.2P), 3.73 (d, .sup.3J.sub.HP=10.6 Hz, 144H, POMe), 6.94 (d, .sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2H), 7.07 (d, .sup.3J.sub.HH=8.1 Hz, 24H, C.sub.1.sup.2H), 7.18 (br d, .sup.3J.sub.HH=8.2 Hz, 36H, C.sub.0.sup.3 and C.sub.1.sup.3H);

    [0702] .sup.13C-{.sup.1H} NMR (151 MHz, CDCl.sub.3) ? (ppm): 33.05 (s, CH.sub.2), 33.64 s, (CH.sub.3N), 49.46 (dd, .sup.1J.sub.CP=157.3, .sup.3J.sub.CP=7.2 Hz, CH.sub.2P), 53.56-51.75 (m, POCH.sub.3), 53.47 (d, .sup.2J.sub.CP=10.3 Hz, C.sub.1.sup.4CH.sub.2), 58.22 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 120.91 (br d, .sup.3J.sub.CP=4.4 Hz, C.sub.0.sup.2 and C.sub.1.sup.2), 129.30 (s, C.sub.0.sup.3), 129.87 (s, C.sub.1.sup.3), 134.10 (br d, .sup.2J.sub.CP=4.5 Hz, C.sub.0.sup.4), 136.22 (s, C.sub.1.sup.4), 149.35 (d, .sup.2J.sub.CP=7.5 Hz, C.sub.1.sup.1), 150.01 (br s, C.sub.0.sup.1).

    Compounds 4-G.SUB.1.(OMe) from 4e

    [0703] ##STR00205##

    [0704] Hexachlorocyclotriphosphazene (56 mg, 0.16 mmol) is added to a solution of compound 4e (1 g, 0.97 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (632 mg, 1.94 mmol). After stirring overnight at 45? C., the mixture is centrifuged, filtered then concentrated under reduced pressure. Dendrimer 4-G.sub.1 was obtained in the form of a transparent oil at a yield of 85%.

    [0705] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.23 (s, P?N), 26.89 (s, POMe), 68.00 (s, PS).

    [0706] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.78 (t, .sup.3J.sub.HH=6.6 Hz, 18H, CH.sub.3), 1.10-1.26 (m, 36H, CH.sub.2), 1.41-1.47 (m, 12H, CH.sub.2), 2.75 (t, .sup.3J.sub.HH=7.6 Hz, 24H, CH.sub.2-C.sub.1.sup.4), 3.04 (t, .sup.3J.sub.HH=7.7 Hz, 24H, CH.sub.2N), 3.09-3.15 (m, 12H, CH.sub.2NP), 3.19 (d, .sup.2J.sub.HP=9.3 Hz, 18H, CH.sub.2P), 3.65-3.79 (m, 144H, POMe), 4.53 (d, .sup.3J.sub.HP=13.1 Hz, 12H, CH.sub.2-C.sub.0.sup.4), 6.95 (d, .sup.3J.sub.HH=8.1 Hz, 12H, C.sub.0.sup.2H), 7.06 (d, .sup.3J.sub.HH=8.2 Hz, 24H, C.sub.1.sup.2H), 7.16 (d, .sup.3J.sub.HH=8.2 Hz, 24H, C.sub.1.sup.2H), 7.22 (d, .sup.3J.sub.HH=8.3 Hz, 24H, C.sub.0.sup.3H).

    Compounds 5-G.SUB.1 .(OMe) from 5e

    [0707] ##STR00206##

    [0708] Hexachlorocyclotriphosphazene (54 mg, 0.15 mmol) is added to a solution of compound 5e (1 g, 0.94 mmol) in THF (30 mL) with Cs.sub.2CO.sub.3 (616 mg, 1.9 mmol). After stirring overnight at 45? C., the mixture is centrifuged, filtered then concentrated under reduced pressure. Dendrimer 5-G.sub.1 was obtained in the form of a transparent oil at a yield of 88%.

    [0709] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.22 (s, P?N), 26.89 (s, POMe), 68.01 (s, PS).

    [0710] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.83 (t, .sup.3J.sub.HH=7.0 Hz, 18H, CH.sub.3), 1.01-1.41 (m, 60H, CH.sub.2), 1.45 (br s, 12H, CH.sub.2), 2.77 (t, .sup.3J.sub.HH=7.5 Hz, 24H, C.sub.1.sup.4CH.sub.2), 3.06 (t, .sup.3J.sub.HH=7.7 Hz, 24H, CH.sub.2N), 3.09-3.15 (m, 12H, CH.sub.2NPS), 3.20 (d, .sup.2J.sub.HP=9.3 Hz, 48H, CH.sub.2P), 3.74 (d, .sup.3J.sub.HP=10.6, 1.5 Hz, 72H, POMe), 3.75 (d, .sup.3J.sub.HP=10.6, 1.5 Hz, 72H, POMe), 4.55 (d, .sup.3J.sub.HP=13.1 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.96 (d, .sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2H), 7.02-7.12 (m, 24H, C.sub.1.sup.2H), 7.18 (d, .sup.3J.sub.HH=8.5 Hz, 24H, C.sub.1.sup.3H), 7.24 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3H).

    [0711] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 14.11 (s, CH.sub.3), 22.61 (s, CH.sub.2), 26.81 (s, CH.sub.2), 27.62 (s, CH.sub.2), 29.18 (s, CH.sub.2), 31.72 (s, CH.sub.2), 33.07 (s C.sub.1.sup.4CH.sub.2), 45.74 (br s, CH.sub.2NS), 49.45 (dd, .sup.1J.sub.CP=157.2, .sup.3J.sub.CP=7.1 Hz, CH.sub.2P), 49.46 (br s, C.sub.0.sup.4CH.sub.2), 52.59-52.71 (m, POMe), 58.30 (t, .sup.3J.sub.CP=7.7 Hz, CH.sub.2N), 120.90 (s, C.sub.0.sup.2H), 121.02 (d, .sup.2J.sub.CP=4.7 Hz, C.sub.0.sup.2H), 129.39 (s, C.sub.0.sup.3H), 129.77 (s, C.sub.1.sup.3H), 134.28 (s, C.sub.0.sup.4), 136.09 (s, C.sub.1.sup.4), 149.54 (d, .sup.2J.sub.CP=7.8 Hz, C.sub.1.sup.1), 150.00 (d, .sup.2J.sub.CP=4.5 Hz, C.sub.0.sup.1).

    [0712] Semi-Convergent Synthesis of Bifunctional 1st Generation Dendrimers

    [0713] Scheme 5 describes the reaction scheme for semi-convergent synthesis of bifunctional 1 st generation dendrimers:

    ##STR00207## ##STR00208##

    Synthesis of Compounds 7a, 7b and 7c

    [0714] Compound 6a, b or c (5.25 mmol) is added to a solution of tert-butyl (4-formylphenyl)carbonate (5 mmol) in DCM (50 mL). After stirring overnight at ambient temperature, the reaction is terminated. Compound 7a, b or c is not isolated and is directly used thereafter.

    Characterization of Compound 7a

    [0715] ##STR00209##

    [0716] .sup.1H RMN (400 MHz, CD.sub.3CN) ? (ppm) 1.39 (s, 9H Boc-NH), 1.55 (s, 9H Boc-O), 3.34 (q, .sup.3J.sub.HH=6.1 Hz, 2H, CH.sub.2NHBoc), 3.65 (m, 2H, CH?NCH.sub.2), 5.42 (s, NHBoc) 7.25 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.2H), 7.80 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.3H), 8.30 (s, 1H, CH?N).

    Characterization of Compound 7b

    [0717] ##STR00210##

    [0718] .sup.1H RMN (400 MHz, CD.sub.2Cl.sub.2) ? (ppm) 1.45 (s, 9H, Boc-NH), 1.57 (s, 9H, Boc-OPh), 3.21 (q, .sup.3J.sub.HH=6.3 Hz, 2H, CH.sub.2NHBoc), 3.47-3.75 (m, 2H, CH?NCH.sub.2), 7.23 (d, .sup.3J.sub.HH=8.7 Hz, 2H, C.sub.0.sup.2H), 7.78 (d, .sup.3J.sub.HH=8.6 Hz, 2H, C.sub.0.sup.3H), 8.32 (s, 1H, HC?N).

    Characterization of Compound 7c

    [0719] ##STR00211##

    [0720] Compound 7c is used directly in the next step.

    Synthesis of Compounds 8a, 8b and 8c

    [0721] Pd/C 10% (250 mg) is added to a solution of compound 7a,b,c (5 mmol) in anhydrous ethanol (50 mL) under 5 bar of hydrogen. After 1.5 hours of stirring at ambient temperature, the reaction is terminated. Compound 8a,b,c is purified over silica gel with a DCM/MeOH gradient at a yield of 70% to 80%.

    Characterization of Compound 8a

    [0722] ##STR00212##

    [0723] .sup.1H RMN (400 MHz, CDCl.sub.3) ? (ppm) 1.45 (s, 4H), 1.56 (s, 2H), 2.74 (t, J=5.8 Hz, 1H), 3.19-3.27 (m, 3H), 3.77 (s, 1H), 5.01 (s, 1H), 7.12 (d, .sup.3J.sub.HH=9.5 Hz, OH), 7.31 (d, .sup.3J.sub.HH=8.3 Hz, 1H).

    [0724] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm) 27.69 (s, Boc-O-Ph), 28.41 (s, Boc-NH), 48.45 (s, N.sub.0CH.sub.2CH.sub.2), 52.82 (s, CH.sub.2CH.sub.2NHBoc), 79.33 (brs, NHCOC(CH.sub.3).sub.3), 83.50 (s, OCOC(CH.sub.3).sub.3), 121.21 (s, C.sub.0.sup.2), 129.03 (s, C.sub.0.sup.3), 137.58 (s, C.sub.0.sup.4), 150.05 (s, C.sub.0.sup.1), 151.96 (s, OC(O)COC(CH.sub.3).sub.3), 156.19 (s, NHC(O)COC(CH.sub.3).sub.3).

    Characterization of Compound 8b

    [0725] ##STR00213##

    [0726] .sup.1H NMR (300 MHz, CD.sub.2Cl.sub.2) ? (ppm): 1.51 (m, 26H, CH.sub.2CH.sub.2CH.sub.2CH.sub.2, Boc-O, Boc-NH), 2.63 (t, J=7.1 Hz, 2H, N.sub.0CH.sub.2), 3.09 (q, J=6.8 Hz, 2H, CH.sub.2NHBoc), 3.80 (s, 2H, C.sub.0.sup.4CH.sub.2), 4.83 (s, 1H, NHBoc), 7.12 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.2H), 7.37 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.3H).

    Characterization of Compound 8c

    [0727] ##STR00214##

    [0728] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 1.43 (s, 9H, NHBoc), 1.55 (s, 9H, NHBoc), 1.65-1.92 (m, 4H, N.sub.0CH.sub.2CH.sub.2, CH.sub.2CH.sub.2NHBoc), 2.45 (s, NH), 2.73 (t, .sup.3J.sub.HH=6.8 Hz, 2H, N.sub.0CH2), 3.21 (q, .sup.3J.sub.HH=5.3 Hz, 2H, CH.sub.2NHBoc), 3.38-3.70 (m, 12H, CH.sub.2O), 3.78 (s, 2H, C.sub.0.sup.4CH.sub.2), 5.13 (s, 1H, NHBoc), 7.11 (d, .sup.3J.sub.HH=8.5 Hz, 2H, C.sub.0.sup.2H), 7.33 (d, .sup.3J.sub.HH=8.1 Hz, 2H, C.sub.0.sup.3H).

    Synthesis of Compounds 9a, 9b and 9c

    [0729] A solution of compound 8a,b,c (4 mmol) with Et.sub.3N (6 mmol) in CH.sub.2Cl.sub.2 (30 mL) is added dropwise to a solution of PSCl.sub.3 (12 mmol) in CH.sub.2Cl.sub.2 (100 mL) with molecular sieve over a duration of 30 min. After 2 h to 12 h of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The crude residue is subsequently purified over silica gel with a 100.fwdarw.98/2 DCM/THF gradient, to give compound 9a,b,c in the form of a transparent oil at a yield of 70 to 85%.

    Characterization of Compound 9a

    [0730] ##STR00215##

    [0731] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 64.17.

    [0732] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.46 (s), 1.58 (s), 3.20-3.61 (m), 4.68 (d, J=15.3 Hz), 7.20 (d, J=8.5 Hz), 7.41 (d, J=8.1 Hz).

    [0733] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 27.69, 28.40, 37.42, 46.47, 50.11, 79.77, 83.82, 121.78, 129.35, 132.41 (d, J=5.6 Hz), 150.96, 151.74, 155.80.

    Characterization of Compound 9b

    [0734] ##STR00216##

    [0735] .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) ? (ppm): 1.23-1.38 (m), 1.45 (s), 1.57 (s), 1.60-1.78 (m), 3.08 (q, J=6.6 Hz), 3.20-3.43 (m), 4.68 (d, J=16.6 Hz), 7.20 (d, J=8.5 Hz), 7.41 (d, J=8.5 Hz).

    [0736] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.2Cl.sub.12) ? (ppm): 63.16.

    [0737] .sup.13C-{.sup.1H} NMR (101 MHz, CD.sub.2Cl.sub.2) ? (ppm): 26.25 (d, J=4.5 Hz), 26.85 (d, J=3.1 Hz), 27.41, 28.14, 29.89, 40.32, 47.40 (d, J=2.4 Hz), 50.21 (d, J=4.5 Hz), 78.56, 83.49, 121.66, 129.05, 133.15 (d, J=5.5 Hz), 150.89, 151.69, 155.76.

    Characterization of Compound 9c

    [0738] ##STR00217##

    [0739] .sup.1H NMR (300 MHz, CDCl.sub.3) ? (ppm): 1.45 (s), 1.58 (s), 1.76 (p, J=6.2 Hz), 1.85-1.99 (m), 3.10-3.29 (m), 3.31-3.76 (m), 4.66 (d, J=16.5 Hz), 4.97 (s), 7.19 (d, J=8.6 Hz), 7.38 (d, J=8.5 Hz).

    [0740] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 63.07.

    Synthesis of Compounds 10a, 10b and 10c

    [0741] Cs.sub.2CO.sub.3 (16.4 mmol) and phenol aminobismethylene phosphonate derived from tyramine (8.2 mmol) are added in succession to a solution of compound 9a,b,c (4 mmol) in THF (30 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The product is subsequently purified by a silica gel chromatographic column (2.5/97.5 to 5/95 MeOH/DCM eluent gradient), to give compound 10a,b,c in the form of a white powder at a yield of 60 to 80%.

    Characterization of Compound 10a

    [0742] ##STR00218##

    [0743] .sup.31P-{.sup.1H} NMR (162 MHz, C.sub.6D.sub.6) ? (ppm): 26.67 (s, POMe), 68.58 (s, PS).

    Characterization of Compound 10b

    [0744] ##STR00219##

    [0745] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.70 (s, POMe), 68.65 (s, PS).

    Characterization of Compound 10c

    [0746] ##STR00220##

    [0747] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 26.68 (s, POMe), 68.80 (s, PS).

    Synthesis of Compounds 11a, 11b and 11c

    [0748] An excess of methylamine in EtOH (8 M) is added to a solution of compound 10 (mmol) in MeOH (10 mL). After stirring overnight at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure.

    [0749] The product is subsequently purified by a silica gel chromatographic column (2.5/97.5 to 5/95 MeOH/DCM eluent gradient), to give compound 11 in the form of a transparent oil at a yield of greater than 80%.

    Characterization of Compound 11a

    [0750] ##STR00221##

    [0751] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.68, 68.75.

    Characterization of Compound 11b

    [0752] ##STR00222##

    [0753] .sup.31P-{.sup.1H} NMR (121 MHz, 00013) ? (ppm): 26.68, 68.75.

    Characterization of Compound 11c

    [0754] ##STR00223##

    [0755] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 26.71, 68.80.

    Synthesis of compounds 11a-G1(NHBoc), 11b-G1(NHBoc and 11c-G1(NHBoc)

    [0756] Compound 11a,b,c (0.72 mmol) and cesium carbonate (1.45 mmol) are added to a solution of N.sub.3P.sub.3Cl.sub.6 (0.1 mmol) in THF. After stirring overnight at a temperature of 40? C., the mixture is centrifuged, filtered and concentrated under reduced pressure. The product is subsequently purified using a silica gel chromatography column to give compound 11a,b,c-G.sub.1(NHBoc) in the form of a transparent oil. The yield is 60 to 80%.

    Characterization of Compound 11a-G.SUB.1.(NHBoc)

    [0757] ##STR00224##

    [0758] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.08 (s, P.sub.0), 26.88 (s, POMe), 68.56 (s, P.sub.1).

    [0759] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.37 (s, 54H, NHBoc), 2.66-2.88 (m, C.sub.1.sup.4CH.sub.2, 24H), 3.00-3.11 (m, C.sub.1.sup.4CH.sub.2 CH.sub.2, 24H), 3.21 (m, 60H, CH.sub.2POMe, CH.sub.2NHBoc), 3.28-3.37 (m, N.sub.0CH2), 3.75 (d, .sup.3J.sub.HP=10.6 Hz, 144H, POMe), 4.58 (d, .sup.3J.sub.HP=12.1 Hz, 12H, C.sub.0.sup.4CH.sub.2), 5.09 (s, 6H, NHBoc), 6.97 (d, .sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2), 7.08 (d, .sup.3J.sub.HH=7.1 Hz, 24H, C.sub.1.sup.2), 7.18 (d, .sup.3J.sub.HH=8.4 Hz, 24H, C.sub.1.sup.3), 7.26 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3).

    [0760] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 28.41 (s, Boc), 33.06 (s, C.sub.1.sup.4CH.sub.2) 38,23 (s, NCH.sub.2CH.sub.2), 45,25 (s, NCH.sub.2CH.sub.2), 48.66 (dd, .sup.1J.sub.CP=157.2, .sup.3J.sub.CP=7.1 Hz, CH.sub.2POMe), 49.57 (brs, C.sub.0.sup.4CH.sub.2), 52.29-53.00 (m, POMe), 58.27 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 79.11 (s, OC(CH.sub.3).sub.3), 120.96 (s, C.sub.0.sup.2), 121.14 (d, .sup.3J.sub.CP=4.5 Hz, C.sub.1.sup.2), 129.69 (s, C.sub.0.sup.3), 129.83 (s, C.sub.1.sup.3), 133.89 (s, C.sub.0.sup.4), 136.31 (s, C.sub.1.sup.4), 149.37 (d, .sup.2J.sub.CP=7.9 Hz, C.sub.1.sup.1), 150.19 (s, C.sub.0.sup.1), 155.86 (s, C?O).

    Characterization of Compound 11b-G.SUB.1 .(NHBoc)

    [0761] ##STR00225##

    [0762] .sup.31P-{.sup.1H} NMR (162 MHz, MeOD) ? (ppm): 8.92, 27.42, 68.63 ppm.

    Characterization of Compound 11c-G.SUB.1.(NHBoc)

    [0763] ##STR00226##

    [0764] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.11 (s, P.sub.0), 26.87 (s, POMe), 68.15 (s, P.sub.1).

    [0765] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.41 (s, 54H, NHBoc), 1.59-1.82 (m, 24H, CH.sub.2CH.sub.2CH.sub.2), 2.77 (m, C.sub.1.sup.4CH.sub.2, 24H), 3.05 (t, .sup.3J.sub.HH=7.7 Hz, 24H, C.sub.1.sup.4CH.sub.2 CH.sub.2), 3.12-3.38 (m, 84H, NCH.sub.2POMe, CH.sub.2NHBoc, N.sub.0CH.sub.2), 3.41-3.64 (m, 60H, CH.sub.2O), 3.74 (.sup.3J.sub.HP=10.6 Hz, 144H, POMe), 4.55 (d, .sup.3J.sub.HP=12.1 Hz, 12H, C.sub.0.sup.4CH.sub.2), 5.15 (s, NHBoc) 6.95 (d.sup.3J.sub.HH=8.2 Hz, 12H, C.sub.0.sup.2), 7.06 (d, .sup.3J.sub.HH 7.1 Hz, 24H, C.sub.1.sup.2), 7.17 (d, .sup.3J.sub.HH=8.4 Hz, 24H, C.sub.1.sup.3), 7.24 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3).

    [0766] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 27.98 (BocHNCH.sub.2CH.sub.2CH.sub.2), 28.45 (s, Boc), 29.66 (N.sub.0CH.sub.2CH.sub.2), 33.03 (s, C.sub.1.sup.4CH.sub.2), 38.42 (s, N.sub.0CH.sub.2CH.sub.2), 43.05 (s, CH.sub.2NHBoc), 49.44 (.sup.1J.sub.CP=157.4, .sup.3J.sub.CP=7.1 Hz, CH.sub.2POMe), 49.65 (brs, C.sub.0.sup.4CH.sub.2), 52.33-52.97 (m, POMe), 58.30 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 68.49 (s, CH.sub.2O), 69.43 (s, CH.sub.2O), 70.08 (s, CH.sub.2O) 70.12 (s, CH.sub.2O), 70.44 (s, CH.sub.2O), 70.49 (s, CH.sub.2O), 78.75 (s, OC(CH.sub.3).sub.3), 120.88 (s, C.sub.0.sup.2), 121.07 (d, .sup.3J.sub.CP=4.7 Hz, C.sub.1.sup.2), 129.44 (s, C.sub.0.sup.3), 129.80 (s, C.sub.1.sup.3), 134.24 (s, C.sub.0.sup.4), 136.16 (s, C.sub.1.sup.4), 149.49 (d, .sup.2J.sub.CP=7.9 Hz, C.sub.1.sup.1), 150.01 (s, C.sub.0.sup.1), 156.04 (s, C?O).

    Synthesis of Compounds 11a-G.SUB.1.(NH.SUB.2.), 11b-G.SUB.1.(NH.SUB.2.) and 11b-G.SUB.1.(NH.SUB.2.)

    [0767] Trifluoroacetic acid (5 mL) is added to a solution of compound 11a,b,c-G.sub.1(NHBoc) in DCM (5 mL). After 10 min of stirring, the mixture is evaporated to dryness then co-evaporated 5 times with 3 mL of DCM to give compound 11a,b,c-G.sub.1(NH.sub.2) in the form of the trifluoroacetate salt, in the form of a transparent oil. The yield is greater than 90%.

    Characterization of Compound 11a-G.SUB.1.(NH.SUB.2.)

    [0768] ##STR00227##

    [0769] .sup.31P-{.sup.1H} NMR (243 MHz, CD.sub.3CN) ? (ppm): 8.74 (s, P.sub.0), 26.00 (s, POMe), 68.65 (s, P.sub.1).

    [0770] .sup.1H NMR (600 MHz, CD.sub.3CN) ? (ppm): 2.81 (t, .sup.3J.sub.HH=7.6 Hz, 24H, C.sub.1.sup.4CH.sub.2), 2.92 (m, 12H, N.sub.0CH2), 3.05 (t, .sup.3J.sub.HH=7.7 Hz, 24H, C.sub.1.sup.4CH.sub.2 CH.sub.2), 3.26 (d, .sup.2J.sub.HP=10.4 Hz, 48H, CH.sub.2POMe), 3.49-3.56 (m, 12H, PNCH.sub.2CH.sub.2NH.sub.3.sup.+), 3.73 (dd, .sup.2J.sub.HP=10.7, J=1.5 Hz, 144H, POMe), 4.55 (d, .sup.3J.sub.HP=12.8 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.91 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2), 7.11 (d, .sup.3J.sub.HH=8.0 Hz, 24H, C.sub.1.sup.2), 7.17-7.28 (m, 36H, C.sub.1.sup.3, C.sub.0.sup.0).

    [0771] .sup.13C-{.sup.1H} NMR (151 MHz, CD.sub.3CN) ? (ppm): 31.38 (s, C.sub.1.sup.4CH.sub.2), 37.34 (s, NCH.sub.2CH.sub.2), 42.63 (s, NCH.sub.2CH.sub.2), 48.66 (dd, .sup.1J.sub.CP=157.2 Hz, .sup.3J.sub.CP=7.1 Hz, CH.sub.2POMe), 49.60 (brs, C.sub.0.sup.4CH.sub.2), 53.01 (d, .sup.2J.sub.CP=7.2 Hz, POMe), 58.10 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 115.13 (q, .sup.1J.sub.CF=286.3 Hz, COOCF.sub.3), 120.81 (s, C.sub.0.sup.2), 121.24 (d, .sup.3J.sub.CP=4.5 Hz, C.sub.1.sup.2), 129.74 (s, C.sub.0.sup.3), 130.10 (s, C.sub.1.sup.3), 134.07 (s, C.sub.0.sup.4), 136.98 (s, C.sub.1.sup.4), 148.98 (d, .sup.2J.sub.CP=7.9 Hz, C.sub.1.sup.1), 149.88 (brs, C.sub.0.sup.1), 157.99 (q, .sup.2J.sub.CF=40.1 Hz, COOCF.sub.3).

    Characterization of Compound 11b-G.SUB.1.(NH.SUB.2.)

    [0772] ##STR00228##

    [0773] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 8.71, 27.42, 68.21).

    Characterization of Compound 11c-G.SUB.1.(NH.SUB.2.)

    [0774] ##STR00229##

    [0775] .sup.1H NMR (400 MHz, CD.sub.3CN) ? (ppm): 1.73 (m, 12H, PNCH.sub.2CH.sub.2), 1.76-1.86 (m, 12H, CH.sub.2CH.sub.2NHBoc), 2.87 (m, 24H, C.sub.1.sup.4CH.sub.2), 3.03 (m, 12H, N.sub.0CHH.sub.2H.sub.2), 3.13-3.22 (m, 24H, C.sub.1.sup.4CH.sub.2CH.sub.2), 3.31 (m, 24H, CH.sub.2O), 3.38 (m, 12H, CH.sub.2CH.sub.2NHBoc), 3.42-3.65 (m, CH.sub.2POMe, OCH.sub.2CH.sub.2O,), 3.79 (d, .sup.2J.sub.HP=10.9 Hz, 144H, POMe), 4.59 (d, .sup.3J.sub.HP=12.8 Hz, 12H, C.sub.0.sup.4CH.sub.2), 6.92 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.2H), 7.14 (d, .sup.3J.sub.HH=7.8 Hz, 24H, C.sub.1.sup.2H), 7.24 (d, .sup.3J.sub.HH=8.4 Hz, 24H, C.sub.1.sup.3H), 7.27-7.36 (d, .sup.3J.sub.HH=8.3 Hz, 12H, C.sub.0.sup.3H).

    [0776] .sup.31P-{.sup.1H} NMR (162 MHz, CD.sub.3CN) ? (ppm): 8.89 (s, P.sub.0), 24.44 (s, POMe), 68.26 (s, P.sub.1).

    Synthesis of Compounds 11a-G.SUB.1.(NH-NAC), 11b-G.SUB.1.(NH-NAC) and 11c-G.SUB.1.(NHNAC)

    [0777] DIPEA is added to a solution of dendrimer 11-G1(NH2) (0.05 mmol) in a DCM/THF mixture until a neutral pH is obtained. Next, a solution of (N-acetyl-S-((3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)thio)cysteine (0.35 mmol) in THF is added. After 3 hours of stirring at ambient temperature, the mixture is concentrated to dryness. The crude residue is subsequently washed 3 times with 15 mL of EtOAc and 2 times with an EtOAc/THF 70/30 mixture to obtain dendrimer 11-G1(NH-NAC). The yield is between 75% and 95%. (N-acetyl-S-((3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)thio)cysteine is obtained according to a procedure described in Cleland J. L. et al., Bioeng. Transl. Med. 2018, 3, 87-101.

    ##STR00230##

    [0778] .sup.1H NMR (400 MHz, THF) ? (ppm): 1.93 (s, 3H, CH.sub.3), 2.79 (s, 4H, C(O)CH.sub.2CH.sub.2C(O)), 2.99-3.33 (m, 6H, SCH.sub.2CH*, C(O)CH.sub.2CH.sub.2S), 4.77 (ddd, .sup.3J.sub.HH=8.0, 7.3, 4.8 Hz, 1H, CH*), 7.52 (d, .sup.3J.sub.HH=7.9 Hz, 1H, NHC(O)CH.sub.3).

    Characterization of Compound 11a-G.SUB.1.(NH-NAC)

    [0779] ##STR00231##

    [0780] .sup.1H NMR (600 MHz, CDCl.sub.3) ? (ppm): 2.01 (s, 18H, NHCOCH.sub.3), 2.37-2.42 (m, 12H, SCH.sub.2CH.sub.2CONH), 2.72-2.94 (m, 36H, SCH.sub.2CH.sub.2CONH, C.sub.1.sup.4CH.sub.2), 2.96-3.42 (m, 108H, C.sub.1.sup.4CH.sub.2 CH.sub.2, NCH.sub.2CH.sub.2NHCO, SCH.sub.2H*, CH.sub.2POMe), 3.75 (d, .sup.2J.sub.HP=10.5 Hz, 144H, POMe), 4.61 (d, .sup.3J.sub.HP=12.7 Hz, 12H, C.sub.0.sup.4CH.sub.2), 4.80 (m, 6H, CH*), 6.82-7.01 (m, 12H, C.sub.0.sup.2H), 7.09 (d, .sup.3J.sub.HH=8.0 Hz, 24H, C.sub.1.sup.2H), 7.20 (d, .sup.3J.sub.HH=7.9 Hz, 24H, C.sub.1.sup.3H), 7.29 (d, .sup.3J.sub.HH=8.4 Hz, 12H, C.sub.0.sup.3H).

    [0781] .sup.31P-{.sup.1H} NMR (243 MHz, CDCl.sub.3) ? (ppm): 8.46 (s, P.sub.0), 26.84 (s, POMe), 68.42 (s, P.sub.1).

    [0782] .sup.13C-{.sup.1H} NMR (151 MHz, CDCl.sub.3) ? (ppm): 23.01 (s, NHCOCH.sub.3), 32.98 (s, C.sub.1.sup.4CH.sub.2), 33.97 (s, SCH2CH2NHCO), 35.81 (s, SCH.sub.2CH.sub.2NHCO), 37.41 (s, NCH.sub.2CH.sub.2NHCO), 41.52 (s, SCH.sub.2CH*), 44.78 (NCH.sub.2CH.sub.2NHCO), 49.48 (dd, .sup.1J.sub.CP=157.2, .sup.3J.sub.CP=7.1 Hz, CH.sub.2POMe), 49.62 (brs, C.sub.0.sup.4CH.sub.2), 52.14 (s, SCH.sub.2CH*), 52.86 (d, .sup.2J.sub.CP=7.2 Hz, POMe), 58.22 (t, .sup.3J.sub.CP=7.7 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 121.12 (s, C.sub.0.sup.2, C.sub.1.sup.2), 129.84 (s, C.sub.0.sup.3), 129.98 (s, C.sub.1.sup.3), 133.84 (s, C.sub.0.sup.4), 136.42 (s, C.sub.1.sup.4), 149.29 (d, .sup.2J.sub.CP=7.9 Hz, C.sub.1.sup.1), 150.09 (brs, C.sub.0.sup.1), 170.64 (brs, NHCOCH.sub.2CH.sub.2S), 171.67 (brs, NHCOCH.sub.3), 171.87 (brs, COOH).

    [0783] The structure of dendrimer 11a-G.sub.1(NH-NAC) is represented in [FIG. 15].

    Characterization of Compound 11b-G.SUB.1 .(NH-NAC)

    [0784] ##STR00232##

    [0785] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.41 (s, P.sub.0), 26.61 (s, POMe), 68.21 (s, P.sub.1).

    [0786] The structure of dendrimer 11 b-G.sub.1(NH-NAC) is represented in [FIG. 16].

    Characterization of Compound 11c-G.SUB.1.(NH-NAC)

    [0787] ##STR00233##

    [0788] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.65-1.80 (m, 24H, CH.sub.2CHH.sub.2CH.sub.2), 2.00 (s, 18H, NHCOCH.sub.3), 2.53 (m, 12H, SCH.sub.2CH.sub.2CONH), 2.69-2.79 (m, 24H, C.sub.1.sup.4CH.sub.2), 2.86-2.96 (m, 12H, SCH.sub.2CH.sub.2CONH), 2.96-3.08 (m, 30H, C.sub.1.sup.4CH.sub.2 CH.sub.2, SCH.sub.2CH*), 3.09-3.57 (m, N.sub.0CH.sub.2, C?ONHCH.sub.2, SCH.sub.2H*, CH.sub.2POMe, CH.sub.2O), 3.72 (d, .sup.2J.sub.HP=10.5 Hz, 144H, POMe), 4.54 (d, .sup.3J.sub.HP=13.3 Hz, 12H, C.sub.0.sup.4CH.sub.2), 4.66 (m, 6H, CH*), 6.94-7.26 (m, 84H, NHCO, NHHOCH.sub.3, C.sub.0.sup.2H, C.sub.1.sup.2H, C.sub.0.sup.3H, C.sub.1.sup.3H).

    [0789] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.13 (s, P.sub.0), 26.84 (s, POMe), 68.06 (s, P.sub.1).

    [0790] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 23.12 (s, 18H, NHCOCH.sub.3), 27.99 (C?OHNCH.sub.2CH.sub.2), 29.05 (s, N.sub.0CH.sub.2CH.sub.2), 32.96 (s, C.sub.1.sup.4CH.sub.2), 34.45 (s, SCH.sub.2CH.sub.2NHCO), 35.89 (s, SCH.sub.2CH.sub.2NHCO), 37.44 (s, NCH.sub.2CH.sub.2NHCO), 42.26 (s, SCH.sub.2CH*), 43.12 (CH.sub.2CH.sub.2NHCO), 49.42 (dd, .sup.1J.sub.CP=157.7, .sup.3J.sub.CP=7.3 Hz, CH.sub.2POMe), 49.66 (brs, C.sub.0.sup.4CH.sub.2), 52.54-52.89 (m, POMe), 52.94 (brs, SCH.sub.2CH*), 58.25 (t, .sup.3J.sub.CP=7.5 Hz, C.sub.1.sup.4CH.sub.2CH.sub.2), 68.45 (s, CH.sub.2O), 69.44 (s, CH.sub.2O), 70.03 (s, CH.sub.2O), 70.36 (s, CH.sub.2O), 70.44 (s, CH.sub.2O), 120.87 (s, C.sub.0.sup.2), 121.04 (d, .sup.3J.sub.CP=4.6 Hz, C.sub.1.sup.2), 129.47 (s, C.sub.0.sup.3), 129.82 (s, C.sub.1.sup.3), 134.28 (s, C.sub.0.sup.4), 136.17 (s, C.sub.1.sup.4), 149.46 (d, .sup.2J.sub.CP=7.9 Hz, C.sub.1.sup.1), 149.99 (s, C.sub.0.sup.1), 170.36 (brs, NHCOCH.sub.2CH.sub.2S), 171.23 (brs, NHCOCH.sub.3), 172.75 (brs, COOH).

    [0791] The structure of dendrimer 11c-G.sub.1(NH-NAC) is represented in [FIG. 17].

    Synthesis of Compounds 11a-G.SUB.1 .(NH-NAC/PO.SUB.3.HNa), 11b-G.SUB.1 .(NH-NAC/PO.SUB.3.HNa) and 11c-G.SUB.1.(NH-NAC/PO.SUB.3.HNa)

    [0792] Bromotrimethylsilane (0.7 mmol) is added dropwise to a solution of dendrimer 11-G1(NH.sub.2-NAC) (0.01 mmol) in acetonitrile (10 mL), at a temperature of 0? C. After stirring overnight at ambient temperature, the solution is concentrated to dryness. Methanol (4 mL) is subsequently added to the dry residue. After one hour of stirring, the powder obtained is filtered then washed 2 times with 5 mL of methanol. The dendrimer is subsequently converted into its sodium salt by adding 1 equivalent of NaOH per surface phosphonic acid. The yield is greater than 95%.

    Characterization of Compound 11a-G.SUB.1.(NH-NAC/PO.SUB.3.HNa)

    [0793] ##STR00234##

    [0794] .sup.31P-{.sup.1H} NMR (243 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 7.23 (s, P.sub.0), 9.59 (s, POMe), 68.64 (s, P.sub.1).

    [0795] 1H NMR (600 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 1.96 (s, 18H, NHCOCH.sub.3), 2.32 (brs, 12H, 12H, SCH.sub.2CH.sub.2CONH), 2.73 (brs, 12H, SCH.sub.2CH.sub.2CONH), 2.87 (m, 6H, CH.sub.2CH*), 2.95-3.33 (m, 1H, C.sub.1.sup.4CH.sub.2CH.sub.2, NCH.sub.2CH.sub.2NHCO, SCH.sub.2H*), 3.50-3.73 (m, 54H, C.sub.1.sup.4CH.sub.2CH.sub.2, CH.sub.2POH), 4.41-4.61 (m, 18H, C.sub.0.sup.4CH.sub.2, NHCHCOOH), 6.85 (s, 12H, C.sub.0.sup.2H), 7.05 (m, 24H, C.sub.1.sup.2H), 7.26 (brs, 36H, C.sub.1.sup.3H, C.sub.0.sup.3H).

    [0796] .sup.13C-{.sup.1H} NMR (151 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 22.05 (s, 18H, NHCOCH.sub.3), 28.86 (s, C.sub.1.sup.4CH.sub.2), 33.16 (s, SCH.sub.2CH.sub.2CONH), 35.13 (s, SCH.sub.2CH.sub.2NHCO), 37.38 (s, NCH.sub.2CH.sub.2NHCO), 39.62 (s, SCH.sub.2CH*), 44.90 (NCH.sub.2CH.sub.2NHCO), 49.67 (brs, C.sub.0.sup.4CH.sub.2), 52.09 (s, CH.sub.2POH), 53.02 (s, SCH.sub.2CH*), 57.35 (brs, C.sub.1.sup.4CH.sub.2CH.sub.2), 121.18 (s, C.sub.0.sup.2), 121.62 (s, C.sub.1.sup.2), 129.92 (s, C.sub.0.sup.3), 130.48 (s, C.sub.1.sup.3), 133.55 (s, C.sub.1.sup.4), 134.42 (s, C.sub.0.sup.4), 149.39 (m, C.sub.0.sup.1), 149.71 (m, C.sub.1.sup.1), 173.20 (brs, NCH.sub.2CH.sub.2NHCO), 173.48 (s, NHCOCH.sub.3), 175.00 (brs, COOH).

    [0797] The structure of dendrimer 11a-G.sub.1(NH-NAC/PO.sub.3HNa) is represented in [FIG. 18].

    Characterization of Compound 11b-G.SUB.1.(NH-NAC/PO.SUB.3.HNa)

    [0798] ##STR00235##

    [0799] .sup.31P-{.sup.1H} NMR (243 MHz, D.sub.2O/CD.sub.3CN) ? (ppm): 7.17 (s, P.sub.0), 9.51 (s, POHNa), 68.69 (s, P.sub.1).

    [0800] The structure of dendrimer 11b-G.sub.1(NH-NAC/PO.sub.3HNa) is represented in [FIG. 19].

    [0801] Characterization of compound 11c-G.sub.1(NH-NAC/PO.sub.3HNa):

    ##STR00236##

    [0802] .sup.1H NMR (400 MHz, D.sub.2O) ? (ppm): 1.63-1.80 (m, 24H, CH.sub.2CH.sub.2CH.sub.2), 2.43-2.66 (m, 12H, SCH.sub.2CH.sub.2CONH), 2.75-3.82 (m, 192H, CH.sub.2), 4.48-4.62 (m, 36H, C.sub.0.sup.4CH.sub.2, CH*), 6.78-7.48 (m, 72H, CH-arom).

    [0803] .sup.31P-{.sup.1H} NMR (162 MHz, D.sub.2O) ? (ppm): 7.18 (s, POHNa), 9.63 (s, P.sub.0), 68.33 (s, P.sub.1).

    [0804] The structure of dendrimer 11c-G.sub.1(NH-NAC/PO.sub.3HNa) is represented in [FIG. 20].

    Synthesis of Layer-Block Dendrimers

    [0805] Scheme 6 describes the reaction scheme of a layer-block dendrimer in which D is methyl and D is (CH.sub.2CH.sub.2O).sub.3CH.sub.3:

    ##STR00237## ##STR00238##

    Synthesis of Compound 12-G.SUB.1.-Boc from 1-G.SUB.1

    [0806] ##STR00239##

    [0807] Cs.sub.2CO.sub.3 (693 mg, 2.130 mmol) and 12-AB-Boc (394 mg, 1.065 mmol) are added in succession to a solution of dendrimer 1-G.sub.1 (125 mg, 0.071 mmol) in THF (20 mL). After stirring 48 hrs at ambient temperature, the mixture is centrifuged, filtered then concentrated under reduced pressure. The product is subsequently purified using silica gel chromatography to give dendrimer 12-G.sub.1-Boc in the form of a transparent oil at a yield of 56%.

    [0808] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 28.44, 33.65, 46.19, 50.23, 51.06, 59.02, 69.72, 70.62, 71.94, 79.83, 120.99, 128.35, 128.91, 129.32, 134.08, 150.07, 155.78.

    [0809] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 1.46-1.48 (m, 108H), 2.78 (d, J=11.0 Hz, 18H), 3.20-3.47 (m, 60H), 3.47-3.89 (m, 120H), 4.50 (s, 36H), 6.98 (d, J=8.6 Hz, 12H), 7.06-7.26 (m, 60H).

    [0810] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.28, 68.11.

    Synthesis of Compound 12-G.SUB.1.-HTFA from 12-G.SUB.1.-Boc

    [0811] ##STR00240##

    [0812] Compound 12-G.sub.1-Boc (120 mg, 0.021 mmol) is dissolved in a CH.sub.2Cl.sub.2/trifluoroacetic acid mixture with a ratio between 50/50 and 70/30 (5 mL). After 30 min of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is subsequently co-evaporated 5 times with 3 mL of CH.sub.2Cl.sub.2 to give dendrimer 12-G.sub.1-HTFA in the form of a yellow oil. The yield is greater than 90%.

    [0813] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 2.70 (d, J=11.0 Hz, 18H), 3.15 (s, 24H), 3.30 (s, 36H), 3.56-3.67 (m, 72H), 3.77 (s, 24H), 4.10 (s, 24H), 4.37 (d, J=12.2 Hz, 12H), 6.88 (d, J=9.0 Hz, 12H), 7.15 (t, J=6.8 Hz, 36H), 7.42 (d, J=8.7 Hz, 24H).

    [0814] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 33.56, 46.19, 50.57, 58.73, 70.09 (d, J=8.5 Hz), 71.52, 114.49 (q), 121.53, 127.62, 129.17, 131.63, 133.73, 149.87, 151.74 (d, J=7.4 Hz), 160.68.

    [0815] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.94, 66.97.

    Synthesis of Compound 12-G.SUB.2.-Boc from 12-G.SUB.1.-HTFA with synthon 1-AB.SUB.2.-Boc

    [0816] ##STR00241##

    [0817] To a 120-mg solution of the trifluoroacetic acid salt of dendrimer 12-G.sub.1-HTFA (0.021 mmol) in CH.sub.2Cl.sub.2 (20 to 50 mL) with DIPEA (0.135 mL, 0.756 mmol), compound 1-AB.sub.2-Boc (180 mg, 0.315 mmol) is added. After 72 hours of stirring at 35? C., the mixture is concentrated to dryness under reduced pressure at ambient temperature. The crude residue is subsequently dissolved in ethyl acetate, filtered, then precipitated in an ether/pentane mixture to give compound 12-G.sub.2-Boc in the form of a yellow oil at a yield of 80%.

    [0818] .sup.31P-{.sup.1H} NMR (121 MHz, CDCl.sub.3) ? (ppm): 8.42, 67.78, 68.00.

    Synthesis of Compound 12-G.SUB.2.-HTFA from 12-G.SUB.2.-Boc

    [0819] ##STR00242##

    [0820] Compound 12-G.sub.2-Boc (100 mg) is dissolved in a CH.sub.2Cl.sub.2/trifluoroacetic acid mixture with a ratio between 50/50 and 70/30 (5 mL). After 30 min of stirring at ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is subsequently co-evaporated 5 times with 3 mL of CH.sub.2Cl.sub.2 to give dendrimer 12-G.sub.2-HTFA in the form of a yellow oil. The yield is greater than 90%.

    [0821] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 8.91, 66.81, 67.1).

    [0822] The structure of dendrimer 12-G.sub.2-HTFA is represented in [FIG. 21].

    [0823] Scheme 7 describes the reaction scheme of a layer-block dendrimer wherein D is methyl and D is octyl:

    ##STR00243##

    Synthesis of Compound 13-G.SUB.2.(OMe) from 1-G.SUB.1 .with the synthon 5e

    [0824] ##STR00244##

    [0825] The compound 1-G.sub.1 (41.2 mg, 0.0235 mmol) is added to a solution of compound 5e (300 mg, 0.282 mmol) in THF (15 mL) with Cs.sub.2CO.sub.3 (184 mg, 0.564 mmol). After stirring overnight at 40? C., the mixture is centrifuged, filtered then concentrated under reduced pressure. Dendrimer 13-G.sub.2(OMe) was obtained in the form of a transparent oil at a yield of 90%.

    [0826] .sup.1H NMR (400 MHz, CDCl.sub.3) ? (ppm): 0.69-0.96 (m, 36H), 1.08-1.40 (m, 120H), 2.73-2.85 (m, 72H), 3.06 (t, J=7.8 Hz, 48H), 3.20 (d, J=9.3 Hz, 114H), 3.74 (d, J=10.3 Hz, 288H), 4.37-4.74 (m, 36H), 6.89-7.39 (m, 168H).

    [0827] .sup.13C-{.sup.1H} NMR (101 MHz, CDCl.sub.3) ? (ppm): 14.10 (d, J=2.6 Hz), 22.59, 26.36-27.03 (m), 27.62, 29.19 (dd, J=14.2, 6.5 Hz), 31.74 (d, J=7.1 Hz), 33.14 (d, J=18.8 Hz), 44.59, 45.86, 48.29-49.03 (m), 49.51, 50.28 (t, J=7.5 Hz), 52.26-52.97 (m), 57.83-58.79 (m), 121.01 (d, J=4.8 Hz), 121.39 (d, J=4.7 Hz), 127.63-130.62 (m), 135.73 (d, J=1.9 Hz), 136.09, 149.32 (d, J=7.2 Hz), 149.53 (d, J=7.3 Hz), 150.42 (d, J=7.7 Hz).

    [0828] .sup.31P-{.sup.1H} NMR (162 MHz, CDCl.sub.3) ? (ppm): 7.97, 26.84, 68.07, 68.68.

    [0829] The structure of dendrimer 13-G.sub.2(OMe) is represented in [FIG. 22].

    Evaluation of the Stability of the Dendrimers According to the Invention

    [0830] The stability of the dendrimers according to the invention at physiological pH was evaluated in comparison with that of a phosphorous dendrimer of the polyphosphorhydrazone type from the prior art (WO 2005/052031 A1).

    [0831] Procedure

    [0832] The compounds were dissolved in water or in an H.sub.2O/D.sub.2O mixture (20 to 50 mg/mL). If necessary, the pH was adjusted and the solutions were stored at 25? C. away from light between each NMR spectrum recording.

    [0833] The results show that the stability of compound 3-G1(ONa) according to the invention at pH=7.2 is far greater than that of the reference compound ABP having a polyphosphorhydrazone backbone and aminobismethylene phosphonic acid terminations (monosodium salt) derived from tyramine. .sup.31p NMR spectroscopy shows a degradation of the compound ABP after 4 days at pH=7.2 at 25? C. (spectrum B of [FIG. 23], with the signal confirming hydrolysis at around 67 ppm; this signal intensifies over time, as indicated in spectra C, D and E). Under the same conditions, compound 3-G1(ONa) remains perfectly stable and no by-product is observed even after 8 months of storage in solution (spectra A to E of [FIG. 24]).

    [0834] The stability of compound 3-G1(ONa) according to the invention at pH=5 is far greater than that of the reference compound ABP having a polyphosphorhydrazone backbone and aminobismethylene phosphonic acid terminations (monosodium salt) derived from tyramine. .sup.31P NMR spectroscopy shows a degradation of the compound ABP after 4 days at pH=5 at 25? C. (spectrum B of [FIG. 25], with the signal confirming hydrolysis at around 67 ppm; this signal intensifies overtime, as indicated in spectra C, D and E). From 10 days onwards, a second signal attesting to degradation is also observed at 48 ppm (spectrum C of [FIG. 25]; this signal intensifies with time as shown in spectra C, D and E). Under the same conditions, compound 3-G1(ONa) remains perfectly stable and no by-product is observed even after 8 months of storage in solution (spectra A to E of [FIG. 26]).

    [0835] The stability of compound 4-G1(ONa) according to the invention at pH=7 is far greater than that of the reference compound ABP having a polyphosphorhydrazone backbone and aminobismethylene phosphonic acid terminations (monosodium salt) derived from tyramine. .sup.31P NMR spectroscopy shows a degradation of the compound ABP after 4 days at pH=7 at 25? C. (spectrum B of [FIG. 23], with the signal confirming hydrolysis at around 67 ppm; this signal intensifies over time, as indicated in spectra C, D and E). Under the same conditions, compound 4-G1(ONa) remains perfectly stable and no by-product is observed even after 4 months of storage in solution (spectra A to E of [FIG. 27]).

    [0836] The stability of compound 5-G1(ONa) according to the invention at pH=7 is far greater than that of the reference compound ABP having a polyphosphorhydrazone backbone and aminobismethylene phosphonic acid terminations (monosodium salt) derived from tyramine. .sup.31P NMR spectroscopy shows a degradation of the compound ABP after 4 days at pH=7 at 25? C. (spectrum B of [FIG. 23], with the signal confirming hydrolysis at around 67 ppm; this signal intensifies over time, as indicated in spectra C, D and E). Under the same conditions, compound 5-G1(ONa) remains perfectly stable and no by-product is observed even after 4 months of storage in solution (spectra A to E of [FIG. 28]).

    [0837] The stability of compound 5-G1(ONa) according to the invention at pH=4 is far greater than that of the reference compound ABP having a polyphosphorhydrazone backbone and aminobismethylene phosphonic acid terminations (monosodium salt) derived from tyramine at pH=5. .sup.31P NMR spectroscopy shows a degradation of the compound ABP after 4 days at pH=5 at 25? C. (spectrum B of [FIG. 25], with the signal confirming hydrolysis at around 67 ppm; this signal intensifies over time, as indicated in spectra C, D and E). At pH=4 and at 25? C., compound 5-G1(ONa) remains perfectly stable and no by-product is observed even after 4 months of storage in solution (spectra A to E of [FIG. 29]).

    Biological Evaluation

    [0838] The activation of primary human monocytes of dendrimer 3-G1(ONa) according to the invention was evaluated.

    [0839] Procedure

    [0840] Human blood from healthy donors is recovered from the ?tablissement fran?ais du sang [French Blood Service] (EFS, Toulouse, France). Peripheral blood mononuclear cells (PBMCs) are subsequently separated from the blood using a density gradient with a Pancoll solution (PANBiotech GmbH) by centrifugation at 1200 rpm for 20 min at 20? C. From the PBMCs, the monocytes are isolated by negative selected with antibodies directed against all blood cells (T cells, B cells, NK cells, dendritic cells, erythrocytes and granulocytes) except for monocytes, using the kit Dynabeads? Untouched? Human Monocytes (Invitrogen). Monocyte purity was verified by flow cytometry to be greater than 90% for each donor with an anti-CD14-APC-Cy7 antibody (Miltenyi Biotec).

    [0841] The freshly purified monocytes were resuspended in a 48-well plate at 1 million per mL in RPMI 1640+GLUTAMAX, penicillin and streptomycin at 100 U/mL and 10% fetal bovine serum (FBS). The dendrimers were added at the start of the cultures, at a concentration of 20 ?M. After 5 days of culture at 37? C., the morphology of the monocytes was analyzed by flow cytometry with a MACSQUANT Q10 cytometer (Miltenyi Biotec). All the cytometry data were analyzed by the Flowlogic? software (Miltenyi Biotec).

    [0842] [FIG. 30] shows the results of the flow cytometry of the morphology (granularity and size) of the monocytes (on the graphs, each dot is a cell). 3 donors were tested, the dendrimer concentration is 20 ?M. The left-hand column relates to the control, non-activated, monocytes. The right-hand column relates to the monocytes cultured for 4 days with dendrimer 3-G1(ONa): the activated monocytes are within the ellipse.

    [0843] A change in morphology (increase in granularity and size) reflects activation of the primary human monocytes. The results show that dendrimer 3-G1(ONa) leads to an increase in granularity and in the size of the primary human monocytes. Moreover, it is noted that a higher proportion of monocytes is in the ellipse of the activated monocytes, with the proportion depending on the donor.